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Plasticity of Human CD4 T Cell Subsets

Jens Geginat, Moira Paroni, Stefano Maglie and 6 more

Frontiers in Immunology · 2014 · Review

doi:10.3389/fimmu.2014.00630

Abstract

Human beings are exposed to a variety of different pathogens, which induce tailored immune responses and consequently generate highly diverse populations of pathogen-specific T cells. CD4(+) T cells have a central role in adaptive immunity, since they provide essential help for both cytotoxic T cell- and antibody-mediated responses. In addition, CD4(+) regulatory T cells are required to maintain self-tolerance and to inhibit immune responses that could damage the host. Initially, two subsets of CD4(+) helper T cells were identified that secrete characteristic effector cytokines and mediate responses against different types of pathogens, i.e., IFN-γ secreting Th1 cells that fight intracellular pathogens, and IL-4 producing Th2 cells that target extracellular parasites. It is now well established that this dichotomy is insufficient to describe the complexity of CD4(+) T cell differentiation, and in particular the human CD4 compartment contains a myriad of T cell subsets with characteristic capacities to produce cytokines and to home to involved tissues. Moreover, it has become increasingly clear that these T cell subsets are not all terminally differentiated cells, but that the majority is plastic and that in particular central memory T cells can acquire different properties and functions in secondary immune responses. In addition, there is compelling evidence that helper T cells can acquire regulatory functions upon chronic stimulation in inflamed tissues. The plasticity of antigen-experienced human T cell subsets is highly relevant for translational medicine, since it opens new perspectives for immune-modulatory therapies for chronic infections, autoimmune diseases, and cancer.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Human CD4+ T cells are critical regulators of the immune system, as drastically demonstrated by HIV-infected individuals that develop susceptibility to opportunistic infections and cancer when virus-dependent depletion reduces CD4+ T cell counts below critical thresholds. CD4+ T cells are very heterogeneous in human adults, because they have been generated in response to a high number of different pathogens and belong to a progressively increasing number of different subsets with specialized functions. Helper T cell subsets are defined by the production of cytokines and/or the expression of characteristic lineage-defining transcription factors (Table 1). Five principal subsets or lineages of CD4+ T cells have been identified so far: T helper (Th)1, Th2, and Th17 cells that target specific classes of pathogens, regulatory T cells that are required to maintain self-tolerance and follicular helper T cells (TFH) that provide help to B cells for antibody production. Heterogeneity is generated upon T cell priming, since naïve T cells have stem-cell-like properties and can differentiate into virtually all different types of effector, memory, or regulatory cells (Table 1). Antigen-experienced T cells are less flexible, but many subsets retain some plasticity and can acquire additional cytokine producing capacities upon antigenic re-stimulation, while others appear to be terminally differentiated. In some cases, T cell functions can even completely change from helper to regulatory functions or vice versa. A caveat of these findings in particular in humans is the enormous heterogeneity of T cells, making it difficult to exclude a selective outgrowth of rare pre-existing precursor cells. Several excellent reviews on the plasticity of mouse T cells have been published in recent years, while human T cell plasticity is less understood, but highly relevant for new therapeutic strategies in immune-mediated diseases.

Terminally Differentiated TH1 and TH2 Effector Cells: The Tip of the Iceberg

Seminal studies have established that CD4+ T cells can differentiate into two types of effector cells with different cytokine producing capacities and functions in humans and mice. Uncommitted naïve T cells that are activated by specialized dendritic cells that produce IL-12 acquire IFN-γ producing capacities. These so-called T helper 1 cells (Th1) are induced upon infections with intracellular pathogens like bacteria or viruses and can activate macrophages to destroy intracellular bacteria. In contrast, naïve T cells primed in the presence of IL-4 undergo a different fate and start to produce IL-4, IL-5, IL-10, and IL-13, but not IFN-γ. These Th2 cells are required to fight extracellular parasites like helminths, but since they induce IgE from B cells they are also involved in allergies. Importantly, it was shown that Th1 versus Th2 differentiation was a crucial decision to resist infections, since BL/6 mice that mount a Th1 response to leishmania were protected, while BALB/c mice that instead induce a Th2 response were highly susceptible. The characteristic cytokines produced by Th1 and Th2 cells, IFN-γ, and IL-4, were further shown to inhibit the differentiation to the opposite differentiation lineage and thus reinforced the original fate decision. The capacity to produce either IFN-γ or IL-4 is stably imprinted by epigenetic modifications like DNA methylation and histone acetylations, ensuring that the cytokine profile of T helper cells is preserved upon cellular division independently of the inducing polarizing cues. Moreover, the generation of Th1 and Th2 cells was shown to depend on the “master” transcription factors T-bet and GATA-3, which induced not only the characteristic cytokines of Th1 and Th2 cells, but also inhibited the differentiation to the alternative lineage. Based on this evidence, it was initially assumed that the differentiation to Th1 and Th2 cells are mutually exclusive and irreversible fate decisions.

TH1 and TH2 Cells Can Acquire New Properties and Functions in Secondary or Chronic Immune Responses

Early studies with human T cell clones showed that IFN-γ and IL-4 production were not necessarily two exclusive features, since some T cells co-produced IFN-γ and IL-4. Notably, human Th1 memory cells are responsive to IL-4 stimulation, and acquire IL-4 producing capacities upon TCR stimulation in the presence of IL-4 without losing IFN-γ production in vitro.

In addition, some T cells in human blood co-express the Th1 and Th2 markers CXCR3 and CCR4 or CRTh2 as well as the lineage-defining transcription factors GATA-3 and T-bet. Consistently, it was shown in mice that histones of these transcription factor genes had both repressive and permissive marks in opposing T cell lineages. In mice, in vivo primed Th2 cells can acquire IFN-γ producing capacities in addition to IL-4 in response to IFN and IL-12, while human blood Th2 cells seem to be less plastic. Moreover, the pathogens and the physiological conditions that induce Th1/2 cells in humans and their role in immune responses remain to be fully defined.

Another early finding that did not fit well into the fixed Th1/Th2 paradigma was the fact that IL-12 could induce IL-10 in Th1 cell clones. IL-10 has potent anti-inflammatory functions and inhibits maturation and T cell stimulatory capacities of APC, thus the concomitant expression of both IFN-γ and IL-10 by T cells was unexpected. Later it was shown that IL-10 produced by T-bet+ Th1 cells was required to inhibit lethal immunopathology upon infections with intracellular parasites, indicating that IL-10-producing Th1 cells prevent overshooting immune responses and the resulting tissue damage in a negative feedback loop. Interestingly, although these IL-10 producing Th1 cells inhibited IL-12 production by APC, they were also able to restrict parasite growth via IFN-γ. However, IFN-γ has also been shown to have some negative effects on T cell responses, providing a possible alternative explanation for IFN-γ production by regulatory T cells. Importantly, IFN-γ/IL-10 co-producing T cells with regulatory functions are present at low frequencies in peripheral blood of healthy donors and respond selectively to persistent pathogens, suggesting that similar to their mouse counterparts they inhibit overshooting immune responses in chronic infections. Thus, Th1 cells can switch from pro-inflammatory effector cells to IL-10 producing type 1 regulatory (Tr1)-like T cells, and this switch is necessary to maintain the integrity of infected tissues in some infections. Complement receptor stimulation, production of IL-27 or IL-12 by myeloid cells, or generation of AHR ligands are possible inductive cues, but also chronic or repetitive antigenic stimulation seems to be required to induce IL-10 production in Th1 cells. Interestingly, a recent paper suggests that IL-10/IFN-γ co-producing T cells can also be generated from Th17 cells under the influence of IL-12 or IL-27 in mice. If IFN-γ/IL-10 co-producing regulatory T cells are stably maintained or are short-lived, if they progressively lose IFN-γ production upon chronic stimulation or revert to Th1 cells upon pathogen clearance is currently unclear (Figure 1).

More recently, additional plasticity of Th2 cells was documented. Thus it was shown that TFH cells were derived from Th2 precursor cells in mouse models of helminth infections. This finding is relevant for Th2 stability, because TFH cells are professional B helper T cells that secrete IL-21 in B cell follicles, express the transcriptional repressor BCL-6 and are thus distinct from conventional Th1 and Th2 cells. Also in human tonsils a fraction of TFH cells express the Th2 marker CRTH2 and produce IL-4. The relationship of Th1 cells with TFH cells is less clear in particular in humans. Some murine TFH cells produce IFN-γ, which induces IgG2a production by B cells, but TFH cells from human tonsils lack IFN-γ production.

Mouse Th2 cells can also switch from IL-4 to IL-9 production upon stimulation with TGF-β. These Th9 cells express the PU.1 transcription factor and can also be directly induced from naïve and memory T cells upon stimulation with TGF-β and IL-4 in humans and mice. Th9 cells can have a pro-inflammatory role in allergic asthma and respond to helminth antigens and allergens in humans. However, IL-9 induction by TGF-β is not restricted to Th2 cells.

Collectively, these findings indicate that both Th1 and Th2 cells can acquire different cytokine producing capacities and functional properties upon antigenic re-stimulation under the influence of cytokines, and are thus much more flexible than originally thought (Figure 1).

Stability of FOXP3+ Tregs is Debated

CD25+ regulatory T cells are required to maintain self-tolerance. They were first identified in mice and later in humans, and the Foxp3 transcription factor was shown to be required for their generation and function. Consistently, IPEX patients, who suffer from a devastating autoimmune disease, were found to have mutations in the Foxp3 gene. Although so-called natural or thymic Foxp3+ Tregs acquire regulatory lineage commitment already upon maturation in the thymus, adaptive, or peripheral Foxp3+ Tregs can be induced from mature CD4+ helper T cells in the periphery under the influence of TGF-β. The transcription factor Helios was proposed to distinguish between these two subsets of natural and induced Foxp3+ Treg, but this concept was not confirmed by others. In humans, CD45RA+CD25+Foxp3+ cells represent a population of bona fide “naïve” and thus thymus-derived Tregs, while CD45RA−Tregs are a mixed population that contain antigen-experienced Tregs of both thymic and peripheral origin. The stability of Foxp3+ Tregs is debated. Lineage tracing of Foxp3+ T cells in mice has lead to conflicting interpretations, since in several studies only very small fractions of Foxp3+ Tregs were found to lose Foxp3 and regulatory functions in vivo. In humans, CD45RA+ but not CD45RA− Tregs could be stably expanded in vitro, suggesting different stabilities of thymic and peripheric Tregs. However, since human Tregs have to be purified according to surface marker expression, it is difficult to exclude a selective outgrowth of Foxp3− cells or of activated effector T cells that have transiently up-regulated Foxp3 upon stimulation.

The functional specialization of Foxp3+ Treg is shaped by the tissue microenvironment, and the induction of transcription factors characteristic for helper T cell lineages in mice allows Tregs to suppress the corresponding T helper cell responses. Thus, STAT3 in Tregs is required to suppress Th17 cells, IRF4 to control Th2 responses while Tregs that regulate TFH cells and antibody responses express BCL-6. Foxp3+ Tregs also acquire T-bet and IFN-γ producing capacities upon stimulation with IL-12, and these Th1regs might be specialized to suppress Th1 responses. Tregs also inhibit anti-tumor CTL responses, and interestingly they can acquire cytotoxic properties in tumor-draining lymph nodes in mice and in vitro in humans, and tumor-infiltrating Tregs are consequently cytotoxic. Similar to helper T cells, Tregs that secrete different types of effector cytokines can be identified according to chemokine receptor expression, and these Treg subsets might specifically suppress different types of immune responses. Human Foxp3+ T cells that produce IL-17 or IFN-γ can be isolated, but while IL-17 producing Treg cells were normally suppressive, IFN-γ producing Tregs had reduced suppressive functions. The conditions that induce human Foxp3+ Tregs to secrete different effector cytokines and the role of these cells in infections, cancer, and autoimmune diseases remain to be fully established.

Heterogeneity and Unstability of TH17 Cells and Its Relevance for Autoimmune Diseases

The discovery of IL-17 producing helper T cells (Th17) in mice and humans and their relative instability has led to a profound re-evaluation of the concept of two terminally differentiated helper T cell subsets. The fact that human CD4+ T cells produce IL-17 was known for a long time. However, it took a decade to realize that these cells represented an independent differentiation lineage, which have unique differentiation requirements and express the lineage-defining transcription factor ROR-γt in mice and RORC2 in humans. Th17 cells are important to fight extracellular bacteria and fungi, since patients that lack Th17 cells have uncontrolled infections with Candida albicans (C. albicans) and Staphylococcus aureus. The discovery of Th17 cells has been complicated by the fact that T cell differentiation to Th1 and Th17 cells relies on shared components of cytokines and their receptors. Thus, it was known that IL-12p40 and IL-12Rβ1 hetero-dimerize with respectively IL-12p35 and IL-12Rβ2 to induce Th1 cells, but later it was realized that they can also associate with respectively IL-23p19 and the IL-23R to promote Th17 responses. The IL-23/IL-23R pathway is involved in many different autoimmune diseases and IL-23-induced Th17 cells are thought play a prominent pathogenic role. Conversely, the contribution of Th1 cells, which were initially thought to drive autoimmune diseases, is now debated. The requirements for Th17 differentiation are more complex than for Th1 and Th2 cells, because IL-17 production in CD4+ T cells can be induced by different cytokine combinations. Initially, TGF-β plus IL-6 was identified in mice, while IL-1β, IL-6, and/or IL-23 were proposed in humans. The de novo Th17 differentiation is very inefficient in humans, and therefore it was suggested that only a cocktail with all four cytokines induces significant Th17 differentiation. Although the role of TGF-β in human Th17 differentiation has been a subject of debate, it was shown in mice that TGF-β induces ROR-γt, while pro-inflammatory cytokines are required to inhibit TGF-β-induced Foxp3 expression and thus Treg generation. The presence of CD4+ T cells co-expressing Foxp3, RORC2, and/or IL-17 in humans is consistent with a role for TGF-β in human Th17 and Treg development. An alternative explanation for the positive role of TGF-β in Th17 differentiation is that TGF-β indirectly favors Th17 cell differentiation by inhibiting Th1 cell development. Indeed, in the absence of TGF-β1, or in the presence of TGF-β3 in mice, pathogenic Th17 cells that co-produce IL-17 and IFN-γ are generated. These Th1/17 cells co-express RORC2 and T-bet, are enriched in autoimmune patients and are specific for both Th1 and Th17-inducing pathogens.

In vitro stability experiments and fate reporter mice suggested that Th17 cells are partially unstable and can switch completely from IL-17 producing Th17 to IFN-γ producing Th1 cells in chronic immune responses. IL-12 can induce this Th17-to-Th1 switch, and CD161 was proposed as a marker that distinguishes these ex-Th17 cells from conventional Th1 cells in humans. However, ex vivo isolated human Th17 cells exhibited stable epigenetic marks at cytokine and transcription factor loci, suggesting that in vivo generated human Th17 cells are not necessarily unstable. Finally, also a very rare population of human T cells that co-produces IL-17 and IL-4 was identified. These Th2/17 cells were proposed to be highly pro-inflammatory in allergic asthma, but their role in immune responses against pathogens remains to be understood.

Th17 cells are highly heterogeneous and produce several effector cytokines besides IL-17. IL-22, a cytokine that promotes epithelial proliferation and barrier function, is produced by some Th17 cells, and IL-22 and IL-17 co-operate to control gram-negative bacteria in the lung. However, a subset of human skin-homing IL-22 producing cells was identified that were distinct from Th17 cells. Indeed, in contrast to IL-17, IL-22 is inhibited by TGF-β and thus how Th17 cells acquire IL-22 producing capacities and if they can even switch from IL-17 to IL-22 production is unclear. Some Th17 and Th22 cells also produce IL-26, a pro-inflammatory cytokine that is not expressed in mice and that also acts selectively on non-hematopoietic cells. A particular relevant cytokine in the pathogenesis of experimental autoimmunity is GM-CSF, which is induced by IL-1β, IL-23, and ROR-γt in mice. Conversely, GM-CSF is inhibited by IL-1β and IL-23 in humans, and is produced by both Th1 and Th17 cells.

Th17 cells also produce high levels of IL-21. IL-6 induces IL-21 in naive T cells upon priming, and IL-21 can induce its own expression and promotes Th17 differentiation in an autocrine manner. Importantly however, IL-21 inhibits GM-CSF and IFN-γ production and promotes instead IL-10 secretion in developing Th17 cells. Consequently, IL-21 promotes the generation of conventional or regulatory Th17 cells, but inhibits the generation of pathogenic Th1/17 cells. Finally, a subset of skin-homing T cells produces IL-9 and responds to C. albicans. Some of these cells co-produce IL-9 and IL-17, while others appear to represent Th9 cells. IL-9 production seems however to be transient, suggesting that these skin-homing Th9 cells are largely unstable.

In summary, the current knowledge indicates that human Th17 cells are highly heterogeneous and partially unstable (Figure 2), and much remains to be learned on the role of different Th17 subsets in immune-mediated diseases.

Regulation of Human T Cell Plasticity in Tissues: The New Frontier

The complex regulation of T helper subsets by cytokines raises the questions where T cells are re-educated and also why this might be important to successfully resist pathogens, since this was a major evolutionary pressure that shaped the human immune system. It was soon realized that stable T cell differentiation often requires repetitive in vitro TCR stimulation in the appropriate cytokine condition, suggesting that immature T cells might be more plastic than more differentiated ones. In vivo primed T cells that are at an intermediate stage of differentiation are central memory T cells (TCM), which similar to naïve T cells have maintained the capacity to home to lymph nodes, produce only low levels of effector cytokines, but produce high levels of IL-2 and IL-21, and expand rapidly to generate secondary waves of effector cells. Conversely, effector memory T cells (TEM) are more differentiated cells since they produce high levels of effector cytokines and home preferentially to inflamed non-lymphoid tissues. Consistent with the view that plasticity is progressively reduced upon T cell differentiation, pre-committed Th1CM cells are more plastic than fully differentiated Th1EM cells, since Th1CM cells generate a substantial population of bona fide Th2 cells upon re-stimulation with IL-4, while Th1EM cells do not revert to Th2 cells, but some acquire IL-4 in addition to IFN-γ producing capacities. This plasticity requires TCR stimulation, since antigen-independent proliferation with homeostatic cytokines resulted exclusively in the generation of Th1 effector cells. Based on these findings it can be speculated that pre-committed TCM cells that cross-react with a different pathogen can be still partially re-educated to a different lineage in lymph nodes, while TEM cells do not easily switch cytokine production, but rather become polyfunctional (Figure 1). Another example of functional plasticity in lymphoid organs is the generation of follicular Foxp3+BCL-6+ Tregs, which are specialized Tregs that control B cell responses. Also Tregs in non-lymphoid tissues acquire tissue-specific properties that are important for their functions. TEM helper cells that are activated by antigen in non-lymphoid tissues can up-regulate CCR7 and home to inflamed lymph nodes where they can influence the secondary immune response and are exposed to a different cytokine milieu. Conversely, tissue-resident memory (TRM) cells have lost sphingosine-1 phosphate receptors and thus also the capacity to re-circulate through the blood to secondary lymphoid organs. TRM belong predominantly to the CD8 compartment, but influenza virus-specific CD4+ TRM can be identified in the lung of humans and mice. If tissue-resident CD4+ T cells are terminally differentiated effector cells or still possess the plasticity to acquire additional cytokine producing capacities remains to be established.

A central organ for the generation of different subsets of Th17 cells is the intestine. Thus, upon self-limiting colitis induced by anti-CD3 injections in mice predominantly IL-10 producing Th17 cells with regulatory functions are induced. Conversely, under conditions that induce IL-23 in the intestine pathogenic IFN-γ and GM-CSF producing Th17 cells are generated that induce colitis. IFN-γ and IL-17 co-producing Th1/17 cells have also been observed in patients with IBD, but very little is known about the regulation of Th17 responses in the human intestine. Th1/17 cells that produce IL-17, IFN-γ, and GM-CSF also drive central nervous system (CNS) inflammation in EAE, a standard mouse model of multiple sclerosis (MS). The CNS is separated from pro-inflammatory T cells by the blood–brain barrier, but spontaneous JC Virus re-activations and progressive multifocal leukoencephalopathy in MS patients treated with anti-VLA-4 antibodies, which block lymphocyte extravasation to the CNS, suggest nevertheless a constant immune surveillance by T cells. How the microenvironment of the CNS influences the properties of CD4+ T cells is the focus of intensive research in mice, but is largely unknown in humans given the difficulties to analyze T cells in the human CNS.

Thus, accumulating evidence underlines the role of the tissue microenvironment in T cell plasticity, and the identification of tissue-specific factors that control T cell functions is likely to have a major impact on translational medicine.

Conclusion and Perspective

The original concept of two terminally differentiated subsets of Th1 and Th2 cells has been substituted by the view that many different T cell subsets with specific cytokine profiles are required to protect us from the different pathogenic insults that were are continuously exposed to. These various T cell subsets possess different degrees of plasticity to acquire new characteristics and functions in secondary or chronic immune responses. In particular, while the stability of Tregs is debated, it is widely accepted that Th17 cells are largely unstable, although exceptions might exist. In addition, human Th17 cells are highly heterogeneous, but the functions of all these different types of Th17 effector cells in protective immune responses and their roles in autoimmune diseases remain to be understood. Another important but poorly understood aspect of T cell plasticity is how different tissue microenvironments impact on human T cell differentiation and stability. The definition of the relative plasticities or stabilities of human T cell subsets in different tissues is highly relevant for future therapeutic interventions in so different immune-related pathologies as chronic viral infections, cancer, and autoimmune diseases.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 151

  1. 1.

    Jung AC Paauw DS. Diagnosing HIV-related disease: using the CD4 count as a guide. J Gen Intern Med (1998 ) 13(2):131–6.

    Not in our library10.1046/j.1525-1497.1998.00031.x

  2. 2.

    Geginat J Paroni M Facciotti F Gruarin P Kastirr I Caprioli F The CD4-centered universe of human T cell subsets. Semin Immunol (2013 ) 25(4):252–62.

    Not in our library10.1016/j.smim.2013.10.012

  3. 3.

    Mosmann TR Coffman RL TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol (1989 ) 7:145–73

    Not in our library10.1146/annurev.iy.07.040189.001045

  4. 4.

    Romagnani S The Th1/Th2 paradigm. Immunol Today (1997 ) 18(6):263–6

    Not in our library10.1016/s0167-5699(97)80019-9

  5. 5.

    Korn T Oukka M Kuchroo V Bettelli E. Th17 cells: effector T cells with inflammatory properties. Semin Immunol (2007 ) 19(6):362–71.

    Not in our library10.1016/j.smim.2007.10.007

  6. 6.

    Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol (2005 ) 6(4):345–52.

    Not in our library10.1038/ni1178

  7. 7.

    Crotty S Follicular helper CD4 T cells (TFH). Annu Rev Immunol (2011 ) 29:621–63

    Not in our library10.1146/annurev-immunol-031210-101400

  8. 8.

    Sallusto F Geginat J Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol (2004 ) 22:745–63.

    Not in our library10.1146/annurev.immunol.22.012703.104702

  9. 9.

    O’Garra A Vieira P. T(H)1 cells control themselves by producing interleukin-10. Nat Rev Immunol (2007 ) 7(6):425–8.

    Not in our library10.1038/nri2097

  10. 10.

    Zhou X Bailey-Bucktrout S Jeker LT Bluestone JA. Plasticity of CD4(+) FoxP3(+) T cells. Curr Opin Immunol (2009 ) 21(3):281–5.

    Not in our library10.1016/j.coi.2009.05.007

  11. 11.

    Zhou L Chong MM Littman DR Plasticity of CD4+ T cell lineage differentiation. Immunity (2009 ) 30(5):646–55

    Not in our library10.1016/j.immuni.2009.05.001

  12. 12.

    Zhu J Paul WE Heterogeneity and plasticity of T helper cells. Cell Res (2010 ) 20(1):4–12

    Not in our library10.1038/cr.2009.138

  13. 13.

    O’Shea JJ Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science (2010 ) 327(5969):1098–102.

    Not in our library10.1126/science.1178334

  14. 14.

    Kleinewietfeld M Hafler DA. The plasticity of human Treg and Th17 cells and its role in autoimmunity. Semin Immunol (2013 ) 25(4):305–12.

    Not in our library10.1016/j.smim.2013.10.009

  15. 15.

    Nizzoli G Krietsch J Weick A Steinfelder S Facciotti F Gruarin P Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T cell responses. Blood (2013 ) 122(6):932–42.

    Not in our library10.1182/blood-2013-04-495424

  16. 16.

    Shortman K Heath WR The CD8+ dendritic cell subset. Immunol Rev (2010 ) 234(1):18–31

    Not in our library10.1111/j.0105-2896.2009.00870.x

  17. 17.

    Robinson DS Hamid Q Ying S Tsicopoulos A Barkans J Bentley AM Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med (1992 ) 326(5):298–304.

    Not in our library10.1056/nejm199201303260504

  18. 18.

    Guler ML Gorham JD Hsieh CS Mackey AJ Steen RG Dietrich WF Genetic susceptibility to Leishmania: IL-12 responsiveness in TH1 cell development [see comments]. Science (1996 ) 271(5251):984–7.

    Not in our library10.1126/science.271.5251.984

  19. 19.

    Kanno Y Vahedi G Hirahara K Singleton K O’Shea JJ. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu Rev Immunol (2012 ) 30:707–31.

    Not in our library10.1146/annurev-immunol-020711-075058

  20. 20.

    Allan RS Zueva E Cammas F Schreiber HA Masson V Belz GT An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature (2012 ) 487(7406):249–53.

    Not in our library10.1038/nature11173

  21. 21.

    Tumes DJ Onodera A Suzuki A Shinoda K Endo Y Iwamura C The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. Immunity (2013 ) 39(5):819–32.

    Not in our library10.1016/j.immuni.2013.09.012

  22. 22.

    Maggi E Parronchi P Manetti R Simonelli C Piccinni MP Rugiu FS Reciprocal regulatory effects of IFN-gamma and IL-4 on the in vitro development of human Th1 and Th2 clones. J Immunol (1992 ) 148(7):2142–7.

    Not in our library

  23. 23.

    Messi M Giacchetto I Nagata K Lanzavecchia A Natoli G Sallusto F. Memory and flexibility of cytokine gene expression as separable properties of human T(H)1 and T(H)2 lymphocytes. Nat Immunol (2003 ) 4(1):78–86.

    Not in our library10.1038/ni872

  24. 24.

    Rivino L Messi M Jarrossay D Lanzavecchia A Sallusto F Geginat J. Chemokine receptor expression identifies Pre-T helper (Th)1, Pre-Th2, and nonpolarized cells among human CD4+ central memory T cells. J Exp Med (2004 ) 200(6):725–35.

    Not in our library10.1084/jem.20040774

  25. 25.
    Stable T-bet+GATA-3+ Th1/Th2 Hybrid Cells Arise In Vivo, Can Develop Directly from Naive Precursors, and Limit Immunopathologic Inflammation · 2013
    No notice
  26. 26.

    Wei G Wei L Zhu J Zang C Hu-Li J Yao Z Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity (2009 ) 30(1):155–67.

    Not in our library10.1016/j.immuni.2008.12.009

  27. 27.

    Hegazy AN Peine M Helmstetter C Panse I Frohlich A Bergthaler A Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions. Immunity (2010 ) 32(1):116–28.

    Not in our library10.1016/j.immuni.2009.12.004

  28. 28.

    Gerosa F Paganin C Peritt D Paiola F Scupoli MT Aste-Amezaga M Interleukin-12 primes human CD4 and CD8 T cell clones for high production of both interferon-gamma and interleukin-10. J Exp Med (1996 ) 183(6):2559–69.

    Not in our library10.1084/jem.183.6.2559

  29. 29.

    Sabat R Grutz G Warszawska K Kirsch S Witte E Wolk K Biology of interleukin-10. Cytokine Growth Factor Rev (2010 ) 21(5):331–44

    Not in our library10.1016/j.cytogfr.2010.09.002

  30. 30.

    Del Prete G De Carli M Almerigogna F Giudizi MG Biagiotti R Romagnani S. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol (1993 ) 150(2):353–60.

    Not in our library

  31. 31.

    Jankovic D Kullberg MC Feng CG Goldszmid RS Collazo CM Wilson M Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J Exp Med (2007 ) 204(2):273–83.

    Not in our library10.1084/jem.20062175

  32. 32.

    Anderson CF Oukka M Kuchroo VJ Sacks D. CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J Exp Med (2007 ) 204(2):285–97.

    Not in our library10.1084/jem.20061886

  33. 33.

    Refaeli Y Van Parijs L Alexander SI Abbas AK. Interferon gamma is required for activation-induced death of T lymphocytes. J Exp Med (2002 ) 196(7):999–1005.

    Not in our library10.1084/jem.20020666

  34. 34.

    Feuerer M Eulenburg K Loddenkemper C Hamann A Huehn J. Self-limitation of Th1-mediated inflammation by IFN-gamma. J Immunol (2006 ) 176(5):2857–63.

    Not in our library10.4049/jimmunol.176.5.2857

  35. 35.

    Haringer B Lozza L Steckel B Geginat J. Identification and characterization of IL-10/IFN-gamma-producing effector-like T cells with regulatory function in human blood. J Exp Med (2009 ) 206(5):1009–17.

    Not in our library10.1084/jem.20082238

  36. 36.

    Cope A Le Friec G Cardone J Kemper C. The Th1 life cycle: molecular control of IFN-gamma to IL-10 switching. Trends Immunol (2011 ) 32(6):278–86.

    Not in our library10.1016/j.it.2011.03.010

  37. 37.

    Roncarolo MG Bacchetta R Bordignon C Narula S Levings MK. Type 1 T regulatory cells. Immunol Rev (2001 ) 182:68–79.

    Not in our library10.1034/j.1600-065x.2001.1820105.x

  38. 38.

    Cardone J Le Friec G Vantourout P Roberts A Fuchs A Jackson I Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells. Nat Immunol (2010 ) 11(9):862–71.

    Not in our library10.1038/ni.1917

  39. 39.

    Murugaiyan G Mittal A Lopez-Diego R Maier LM Anderson DE Weiner HL. IL-27 is a key regulator of IL-10 and IL-17 production by human CD4+ T cells. J Immunol (2009 ) 183(4):2435–43.

    Not in our library10.4049/jimmunol.0900568

  40. 40.

    Ansari NA Kumar R Gautam S Nylen S Singh OP Sundar S IL-27 and IL-21 are associated with T cell IL-10 responses in human visceral leishmaniasis. J Immunol (2011 ) 186(7):3977–85.

    Not in our library10.4049/jimmunol.1003588

  41. 41.

    Gandhi R Kumar D Burns EJ Nadeau M Dake B Laroni A Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells. Nat Immunol (2010 ) 11(9):846–53.

    Not in our library10.1038/ni.1915

  42. 42.
    Interleukin-10 Production by Th1 Cells Requires Interleukin-12-Induced STAT4 Transcription Factor and ERK MAP Kinase Activation by High Antigen Dose · 2009
    No notice
  43. 43.

    Parish IA Marshall HD Staron MM Lang PA Brustle A Chen JH Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1. J Clin Invest (2014 ) 124(8):3455–68.

    Not in our library10.1172/jci66108

  44. 44.

    Heinemann C Heink S Petermann F Vasanthakumar A Rothhammer V Doorduijn E IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1. Nat Commun (2014 ) 5:3770.

    Not in our library10.1038/ncomms4770

  45. 45.

    Zaretsky AG Taylor JJ King IL Marshall FA Mohrs M Pearce EJ. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med (2009 ) 206(5):991–9.

    Not in our library10.1084/jem.20090303

  46. 46.

    Chtanova T Tangye SG Newton R Frank N Hodge MR Rolph MS T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J Immunol (2004 ) 173(1):68–78

    Not in our library10.4049/jimmunol.173.1.68

  47. 47.

    Nurieva RI Chung Y Martinez GJ Yang XO Tanaka S Matskevitch TD Bcl6 mediates the development of T follicular helper cells. Science (2009 ) 325(5943):1001–5.

    Not in our library10.1126/science.1176676

  48. 48.

    Johansson-Lindbom B Ingvarsson S Borrebaeck CA. Germinal centers regulate human Th2 development. J Immunol (2003 ) 171(4):1657–66.

    Not in our library10.4049/jimmunol.171.4.1657

  49. 49.

    Pepper M Pagan AJ Igyarto BZ Taylor JJ Jenkins MK. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity (2011 ) 35(4):583–95.

    Not in our library10.1016/j.immuni.2011.09.009

  50. 50.

    Hale JS Youngblood B Latner DR Mohammed AU Ye L Akondy RS Distinct memory CD4+ T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection. Immunity (2013 ) 38(4):805–17.

    Not in our library10.1016/j.immuni.2013.02.020

  51. 51.

    Reinhardt RL Liang HE Locksley RM. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol (2009 ) 10(4):385–93.

    Not in our library10.1038/ni.1715

  52. 52.

    Croft M Swain SL. B cell response to T helper cell subsets. II. Both the stage of T cell differentiation and the cytokines secreted determine the extent and nature of helper activity. J Immunol (1991 ) 147(11):3679–89.

    Not in our library

  53. 53.

    Veldhoen M Uyttenhove C van Snick J Helmby H Westendorf A Buer J Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol (2008 ) 9(12):1341–6.

    Not in our library10.1038/ni.1659

  54. 54.

    Chang HC Sehra S Goswami R Yao W Yu Q Stritesky GL The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol (2010 ) 11(6):527–34.

    Not in our library10.1038/ni.1867

  55. 55.
    Human CD4 memory T cells can become CD4+IL-9+ T cells. · 2010
    Not checked
  56. 56.

    Dardalhon V Awasthi A Kwon H Galileos G Gao W Sobel RA IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol (2008 ) 9(12):1347–55.

    Not in our library10.1038/ni.1677

  57. 57.

    Staudt V Bothur E Klein M Lingnau K Reuter S Grebe N Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity (2010 ) 33(2):192–202.

    Not in our library10.1016/j.immuni.2010.07.014

  58. 58.

    Anuradha R George PJ Hanna LE Chandrasekaran V Kumaran P Nutman TB IL-4-, TGF-beta-, and IL-1-dependent expansion of parasite antigen-specific Th9 cells is associated with clinical pathology in human lymphatic filariasis. J Immunol (2013 ) 191(5):2466–73.

    Not in our library10.4049/jimmunol.1300911

  59. 59.

    Xie J Lotoski LC Chooniedass R Su RC Simons FE Liem J Elevated antigen-driven IL-9 responses are prominent in peanut allergic humans. PLoS One (2012 ) 7(10):e45377.

    Not in our library10.1371/journal.pone.0045377

  60. 60.

    Beriou G Bradshaw EM Lozano E Costantino CM Hastings WD Orban T TGF-beta induces IL-9 production from human Th17 cells. J Immunol (2010 ) 185(1):46–54.

    Not in our library10.4049/jimmunol.1000356

  61. 61.

    Sakaguchi S Sakaguchi N Asano M Itoh M Toda M Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol (1995 ) 155(3):1151–64.

    Not in our library

  62. 62.

    Stephens LA Mottet C Mason D Powrie F. Human CD4(+)CD25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur J Immunol (2001 ) 31(4):1247–54.

    Not in our library10.1002/1521-4141(200104)31:4<1247::aid-immu1247>3.0.co;2-m

  63. 63.

    Hori S Nomura T Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science (2003 ) 299(5609):1057–61.

    Not in our library10.1126/science.1079490

  64. 64.

    Fontenot JD Rasmussen JP Williams LM Dooley JL Farr AG Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity (2005 ) 22(3):329–41.

    Not in our library10.1016/j.immuni.2005.01.016

  65. 65.

    Gambineri E Torgerson TR Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol (2003 ) 15(4):430–5.

    Not in our library10.1097/00002281-200307000-00010

  66. 66.

    Sakaguchi S Ono M Setoguchi R Yagi H Hori S Fehervari Z Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev (2006 ) 212:8–27.

    Not in our library10.1111/j.0105-2896.2006.00427.x

  67. 67.

    Fantini MC Becker C Tubbe I Nikolaev A Lehr HA Galle P Transforming growth factor beta induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis. Gut (2006 ) 55(5):671–80.

    Not in our library10.1136/gut.2005.072801

  68. 68.

    Tran DQ Ramsey H Shevach EM. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood (2007 ) 110(8):2983–90.

    Not in our library10.1182/blood-2007-06-094656

  69. 69.

    Gottschalk RA Corse E Allison JP Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J Immunol (2012 ) 188(3):976–80

    Not in our library10.4049/jimmunol.1102964

  70. 70.

    Himmel ME MacDonald KG Garcia RV Steiner TS Levings MK Helios+ and Helios- cells coexist within the natural FOXP3+ T regulatory cell subset in humans. J Immunol (2013 ) 190(5):2001–8

    Not in our library10.4049/jimmunol.1201379

  71. 71.

    Thornton AM Korty PE Tran DQ Wohlfert EA Murray PE Belkaid Y Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol (2010 ) 184(7):3433–41

    Not in our library10.4049/jimmunol.0904028

  72. 72.

    Hoffmann P Eder R Boeld TJ Doser K Piseshka B Andreesen R Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood (2006 ) 108(13):4260–7.

    Not in our library10.1182/blood-2006-06-027409

  73. 73.

    Hori S. Regulatory T cell plasticity: beyond the controversies. Trends Immunol (2011 ) 32(7):295–300.

    Not in our library10.1016/j.it.2011.04.004

  74. 74.

    Sawant DV Vignali DA Once a Treg, always a Treg? Immunol Rev (2014 ) 259(1):173–91

    Not in our library10.1111/imr.12173

  75. 75.

    Schmidl C Hansmann L Andreesen R Edinger M Hoffmann P Rehli M. Epigenetic reprogramming of the RORC locus during in vitro expansion is a distinctive feature of human memory but not naive Treg. Eur J Immunol (2011 ) 41(5):1491–8.

    Not in our library10.1002/eji.201041067

  76. 76.

    Burzyn D Benoist C Mathis D Regulatory T cells in nonlymphoid tissues. Nat Immunol (2013 ) 14(10):1007–13

    Not in our library10.1038/ni.2683

  77. 77.

    Chaudhry A Rudra D Treuting P Samstein RM Liang Y Kas A CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science (2009 ) 326(5955):986–91.

    Not in our library10.1126/science.1172702

  78. 78.

    Zheng Y Chaudhry A Kas A deRoos P Kim JM Chu TT Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature (2009 ) 458(7236):351–6.

    Not in our library10.1038/nature07674

  79. 79.

    Linterman MA Pierson W Lee SK Kallies A Kawamoto S Rayner TF Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med (2011 ) 17(8):975–82.

    Not in our library10.1038/nm.2425

  80. 80.

    Chung Y Tanaka S Chu F Nurieva RI Martinez GJ Rawal S Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med (2011 ) 17(8):983–8.

    Not in our library10.1038/nm.2426

  81. 81.

    Antony PA Piccirillo CA Akpinarli A Finkelstein SE Speiss PJ Surman DR CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol (2005 ) 174(5):2591–601.

    Not in our library10.4049/jimmunol.174.5.2591

  82. 82.

    Boissonnas A Scholer-Dahirel A Simon-Blancal V Pace L Valet F Kissenpfennig A Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes. Immunity (2010 ) 32(2):266–78.

    Not in our library10.1016/j.immuni.2009.11.015

  83. 83.

    Grossman WJ Verbsky JW Tollefsen BL Kemper C Atkinson JP Ley TJ. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood (2004 ) 104(9):2840–8.

    Not in our library10.1182/blood-2004-03-0859

  84. 84.

    Cao X Cai SF Fehniger TA Song J Collins LI Piwnica-Worms DR Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity (2007 ) 27(4):635–46.

    Not in our library10.1016/j.immuni.2007.08.014

  85. 85.

    Duhen T Duhen R Lanzavecchia A Sallusto F Campbell DJ. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood (2012 ) 119(19):4430–40.

    Not in our library10.1182/blood-2011-11-392324

  86. 86.

    Ayyoub M Deknuydt F Raimbaud I Dousset C Leveque L Bioley G Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the T(H)17 lineage-specific transcription factor RORgamma t. Proc Natl Acad Sci U S A (2009 ) 106(21):8635–40.

    Not in our library10.1073/pnas.0900621106

  87. 87.

    Dominguez-Villar M Baecher-Allan CM Hafler DA. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat Med (2011 ) 17(6):673–5.

    Not in our library10.1038/nm.2389

  88. 88.

    Voo KS Wang YH Santori FR Boggiano C Arima K Bover L Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci U S A (2009 ) 106(12):4793–8.

    Not in our library10.1073/pnas.0900408106

  89. 89.

    Park H Li Z Yang XO Chang SH Nurieva R Wang YH A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol (2005 ) 6(11):1133–41.

    Not in our library10.1038/ni1261

  90. 90.

    Harrington LE Hatton RD Mangan PR Turner H Murphy TL Murphy KM Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol (2005 ) 6(11):1123–32.

    Not in our library10.1038/ni1254

  91. 91.

    Acosta-Rodriguez EV Rivino L Geginat J Jarrossay D Gattorno M Lanzavecchia A Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol (2007 ) 8(6):639–46.

    Not in our library10.1038/ni1467

  92. 92.

    Annunziato F Cosmi L Santarlasci V Maggi L Liotta F Mazzinghi B Phenotypic and functional features of human Th17 cells. J Exp Med (2007 ) 204(8):1849–61.

    Not in our library10.1084/jem.20070663

  93. 93.

    Yao Z Painter SL Fanslow WC Ulrich D Macduff BM Spriggs MK Human IL-17: a novel cytokine derived from T cells. J Immunol (1995 ) 155(12):5483–6.

    Not in our library

  94. 94.

    Ivanov II McKenzie BS Zhou L Tadokoro CE Lepelley A Lafaille JJ The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell (2006 ) 126(6):1121–33.

    Not in our library10.1016/j.cell.2006.07.035

  95. 95.

    Unutmaz D. RORC2: the master of human Th17 cell programming. Eur J Immunol (2009 ) 39(6):1452–5.

    Not in our library10.1002/eji.200939540

  96. 96.

    Ma CS Chew GY Simpson N Priyadarshi A Wong M Grimbacher B Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med (2008 ) 205(7):1551–7.

    Not in our library10.1084/jem.20080218

  97. 97.

    McKenzie BS Kastelein RA Cua DJ. Understanding the IL-23-IL-17 immune pathway. Trends Immunol (2006 ) 27(1):17–23.

    Not in our library10.1016/j.it.2005.10.003

  98. 98.

    Duerr RH Taylor KD Brant SR Rioux JD Silverberg MS Daly MJ A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science (2006 ) 314(5804):1461–3.

    Not in our library10.1126/science.1135245

  99. 99.

    Sarin R Wu X Abraham C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc Natl Acad Sci U S A (2011 ) 108(23):9560–5.

    Not in our library10.1073/pnas.1017854108

  100. 100.

    Nair RP Duffin KC Helms C Ding J Stuart PE Goldgar D Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet (2009 ) 41(2):199–204.

    Not in our library10.1038/ng.311

  101. 101.

    McGeachy MJ Chen Y Tato CM Laurence A Joyce-Shaikh B Blumenschein WM The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol (2009 ) 10(3):314–24.

    Not in our library10.1038/ni.1698

  102. 102.

    El-Behi M Ciric B Dai H Yan Y Cullimore M Safavi F The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol (2011 ) 12(6):568–75.

    Not in our library10.1038/ni.2031

  103. 103.

    McGeachy MJ Bak-Jensen KS Chen Y Tato CM Blumenschein W McClanahan T TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol (2007 ) 8(12):1390–7.

    Not in our library10.1038/ni1539

  104. 104.

    Yen D Cheung J Scheerens H Poulet F McClanahan T McKenzie B IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest (2006 ) 116(5):1310–6.

    Not in our library10.1172/jci21404

  105. 105.

    Veldhoen M Hocking RJ Atkins CJ Locksley RM Stockinger B TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity (2006 ) 24(2):179–89

    Not in our library10.1016/j.immuni.2006.01.001

  106. 106.

    Acosta-Rodriguez EV Napolitani G Lanzavecchia A Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol (2007 ) 8(9):942–9.

    Not in our library10.1038/ni1496

  107. 107.

    Cosmi L De Palma R Santarlasci V Maggi L Capone M Frosali F Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J Exp Med (2008 ) 205(8):1903–16.

    Not in our library10.1084/jem.20080397

  108. 108.

    Manel N Unutmaz D Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol (2008 ) 9(6):641–9.

    Not in our library10.1038/ni.1610

  109. 109.

    Volpe E Servant N Zollinger R Bogiatzi SI Hupe P Barillot E A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol (2008 ) 9(6):650–7.

    Not in our library10.1038/ni.1613

  110. 110.

    Zhou L Lopes JE Chong MM Ivanov II Min R Victora GD TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature (2008 ) 453(7192):236–40.

    Not in our library10.1038/nature06878

  111. 111.

    Santarlasci V Maggi L Capone M Frosali F Querci V De Palma R TGF-beta indirectly favors the development of human Th17 cells by inhibiting Th1 cells. Eur J Immunol (2009 ) 39(1):207–15.

    Not in our library10.1002/eji.200838748

  112. 112.

    Ghoreschi K Laurence A Yang XP Tato CM McGeachy MJ Konkel JE Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature (2010 ) 467(7318):967–71.

    Not in our library10.1038/nature09447

  113. 113.

    Lee Y Awasthi A Yosef N Quintana FJ Xiao S Peters A Induction and molecular signature of pathogenic TH17 cells. Nat Immunol (2012 ) 13(10):991–9.

    Not in our library10.1038/ni.2416

  114. 114.

    Zielinski CE Mele F Aschenbrenner D Jarrossay D Ronchi F Gattorno M Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta. Nature (2012 ) 484(7395):514–8.

    Not in our library10.1038/nature10957

  115. 115.

    Duhen T Campbell DJ. IL-1beta promotes the differentiation of polyfunctional human CCR6+CXCR3+ Th1/17 cells that are specific for pathogenic and commensal microbes. J Immunol (2014 ) 193(1):120–9.

    Not in our library10.4049/jimmunol.1302734

  116. 116.

    Hirota K Duarte JH Veldhoen M Hornsby E Li Y Cua DJ Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol (2011 ) 12(3):255–63.

    Not in our library10.1038/ni.1993

  117. 117.

    Lexberg MH Taubner A Albrecht I Lepenies I Richter A Kamradt T IFN-gamma and IL-12 synergize to convert in vivo generated Th17 into Th1/Th17 cells. Eur J Immunol (2010 ) 40(11):3017–27.

    Not in our library10.1002/eji.201040539

  118. 118.

    Maggi L Santarlasci V Capone M Rossi MC Querci V Mazzoni A Distinctive features of classic and nonclassic (Th17 derived) human Th1 cells. Eur J Immunol (2012 ) 42(12):3180–8.

    Not in our library10.1002/eji.201242648

  119. 119.

    Cohen CJ Crome SQ MacDonald KG Dai EL Mager DL Levings MK. Human Th1 and Th17 cells exhibit epigenetic stability at signature cytokine and transcription factor loci. J Immunol (2011 ) 187(11):5615–26.

    Not in our library10.4049/jimmunol.1101058

  120. 120.

    Cosmi L Maggi L Santarlasci V Capone M Cardilicchia E Frosali F Identification of a novel subset of human circulating memory CD4(+) T cells that produce both IL-17A and IL-4. J Allergy Clin Immunol (2010 ) 125(1):e1–4.

    Not in our library10.1016/j.jaci.2009.10.012

  121. 121.

    Zenewicz LA Flavell RA. IL-22 and inflammation: leukin’ through a glass onion. Eur J Immunol (2008 ) 38(12):3265–8.

    Not in our library10.1002/eji.200838655

  122. 122.

    Liang SC Tan XY Luxenberg DP Karim R Dunussi-Joannopoulos K Collins M Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med (2006 ) 203(10):2271–9.

    Not in our library10.1084/jem.20061308

  123. 123.

    Ma HL Liang S Li J Napierata L Brown T Benoit S IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J Clin Invest (2008 ) 118(2):597–607.

    Not in our library10.1172/jci33263

  124. 124.

    Aujla SJ Chan YR Zheng M Fei M Askew DJ Pociask DA IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med (2008 ) 14(3):275–81.

    Not in our library10.1038/nm1710

  125. 125.

    Duhen T Geiger R Jarrossay D Lanzavecchia A Sallusto F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol (2009 ) 10(8):857–63.

    Not in our library10.1038/ni.1767

  126. 126.

    Trifari S Kaplan CD Tran EH Crellin NK Spits H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol (2009 ) 10(8):864–71.

    Not in our library10.1038/ni.1770

  127. 127.

    Rutz S Noubade R Eidenschenk C Ota N Zeng W Zheng Y Transcription factor c-Maf mediates the TGF-beta-dependent suppression of IL-22 production in T(H)17 cells. Nat Immunol (2011 ) 12(12):1238–45.

    Not in our library10.1038/ni.2134

  128. 128.

    Dambacher J Beigel F Zitzmann K De Toni EN Goke B Diepolder HM The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut (2009 ) 58(9):1207–17.

    Not in our library10.1136/gut.2007.130112

  129. 129.

    Codarri L Gyulveszi G Tosevski V Hesske L Fontana A Magnenat L RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol (2011 ) 12(6):560–7.

    Not in our library10.1038/ni.2027

  130. 130.

    Noster R Riedel R Mashreghi MF Radbruch H Harms L Haftmann C IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells. Sci Transl Med (2014 ) 6(241):241ra80.

    Not in our library10.1126/scitranslmed.3008706

  131. 131.

    Kastirr I Maglie S Paroni M Alfen JS Nizzoli G Sugliano E IL-21 is a central memory T cell-associated cytokine that inhibits the generation of pathogenic Th1/17 effector cells. J Immunol (2014 ) 193(7):3322–31.

    Not in our library10.4049/jimmunol.1400775

  132. 132.

    Zhou L Ivanov II Spolski R Min R Shenderov K Egawa T IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol (2007 ) 8(9):967–74.

    Not in our library10.1038/ni1488

  133. 133.

    Caprioli F Sarra M Caruso R Stolfi C Fina D Sica G Autocrine regulation of IL-21 production in human T lymphocytes. J Immunol (2008 ) 180(3):1800–7.

    Not in our library10.4049/jimmunol.180.3.1800

  134. 134.

    Nurieva R Yang XO Martinez G Zhang Y Panopoulos AD Ma L Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature (2007 ) 448(7152):480–3.

    Not in our library10.1038/nature05969

  135. 135.

    Korn T Bettelli E Gao W Awasthi A Jager A Strom TB IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature (2007 ) 448(7152):484–7.

    Not in our library10.1038/nature05970

  136. 136.

    Yang L Anderson DE Baecher-Allan C Hastings WD Bettelli E Oukka M IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature (2008 ) 454(7202):350–2.

    Not in our library10.1038/nature07021

  137. 137.

    Peters A Lee Y Kuchroo VK. The many faces of Th17 cells. Curr Opin Immunol (2011 ) 23(6):702–6.

    Not in our library10.1016/j.coi.2011.08.007

  138. 138.

    Esplugues E Huber S Gagliani N Hauser AE Town T Wan YY Control of TH17 cells occurs in the small intestine. Nature (2011 ) 475(7357):514–8.

    Not in our library10.1038/nature10228

  139. 139.

    Schlapbach C Gehad A Yang C Watanabe R Guenova E Teague JE Human TH9 cells are skin-tropic and have autocrine and paracrine proinflammatory capacity. Sci Transl Med (2014 ) 6(219):219ra8.

    Not in our library10.1126/scitranslmed.3007828

  140. 140.

    Lohning M Richter A Radbruch A. Cytokine memory of T helper lymphocytes. Adv Immunol (2002 ) 80:115–81.

    Not in our library10.1016/s0065-2776(02)80014-1

  141. 141.

    Sallusto F Kremmer E Palermo B Hoy A Ponath P Qin S Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells. Eur J Immunol (1999 ) 29(6):2037–45.

    Not in our library10.1002/(sici)1521-4141(199906)29:06<2037::aid-immu2037>3.3.co;2-m

  142. 142.

    Guarda G Hons M Soriano SF Huang AY Polley R Martin-Fontecha A L-selectin-negative CCR7- effector and memory CD8+ T cells enter reactive lymph nodes and kill dendritic cells. Nat Immunol (2007 ) 8(7):743–52.

    Not in our library10.1038/ni1469

  143. 143.

    Shin H Iwasaki A. Tissue-resident memory T cells. Immunol Rev (2013 ) 255(1):165–81.

    Not in our library10.1111/imr.12087

  144. 144.

    Turner DL Bickham KL Thome JJ Kim CY D’Ovidio F Wherry EJ Lung niches for the generation and maintenance of tissue-resident memory T cells. Mucosal Immunol (2014 ) 7(3):501–10.

    Not in our library10.1038/mi.2013.67

  145. 145.

    Sathaliyawala T Kubota M Yudanin N Turner D Camp P Thome JJ Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity (2013 ) 38(1):187–97.

    Not in our library10.1016/j.immuni.2012.09.020

  146. 146.

    Huber S Gagliani N Flavell RA. Life, death, and miracles: Th17 cells in the intestine. Eur J Immunol (2012 ) 42(9):2238–45.

    Not in our library10.1002/eji.201242619

  147. 147.

    Kullberg MC Jankovic D Feng CG Hue S Gorelick PL McKenzie BS IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med (2006 ) 203(11):2485–94.

    Not in our library10.1084/jem.20061082

  148. 148.
    Dysregulated Hematopoietic Stem and Progenitor Cell Activity Promotes Interleukin-23-Driven Chronic Intestinal Inflammation · 2012
    No notice
  149. 149.

    Fletcher JM Lalor SJ Sweeney CM Tubridy N Mills KH T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol (2010 ) 162(1):1–11

    Not in our library10.1111/j.1365-2249.2010.04143.x

  150. 150.

    Engelhardt B Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol (2012 ) 33(12):579–89.

    Not in our library10.1016/j.it.2012.07.004

  151. 151.

    Berger JR Houff S. Progressive multifocal leukoencephalopathy: lessons from AIDS and natalizumab. Neurol Res (2006 ) 28(3):299–305.

    Not in our library10.1179/016164106x98198

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