How do Regulatory T Cells Work?

Abstract

CD4 + T cells are commonly divided into regulatory T (Treg) cells and conventional T helper (Th) cells. Th cells control adaptive immunity against pathogens and cancer by activating other effector immune cells. Treg cells are defined as CD4 + T cells in charge of suppressing potentially deleterious activities of Th cells. This review briefly summarizes the current knowledge in the Treg field and defines some key questions that remain to be answered. Suggested functions for Treg cells include: prevention of autoimmune diseases by maintaining self‐tolerance; suppression of allergy, asthma and pathogen‐induced immunopathology; feto‐maternal tolerance; and oral tolerance. Identification of Treg cells remains problematic, because accumulating evidence suggests that all the presently‐used Treg markers (CD25, CTLA‐4, GITR, LAG‐3, CD127 and Foxp3) represent general T‐cell activation markers, rather than being truly Treg‐specific. Treg‐cell activation is antigen‐specific, which implies that suppressive activities of Treg cells are antigen‐dependent. It has been proposed that Treg cells would be self‐reactive, but extensive TCR repertoire analysis suggests that self‐reactivity may be the exception rather than the rule. The classification of Treg cells as a separate lineage remains controversial because the ability to suppress is not an exclusive Treg property. Suppressive activities attributed to Treg cells may in reality, at least in some experimental settings, be exerted by conventional Th cell subsets, such as Th1, Th2, Th17 and T follicular (Tfh) cells. Recent reports have also demonstrated that Foxp3 + Treg cells may differentiate in vivo into conventional effector Th cells, with or without concomitant downregulation of Foxp3.

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References 159

1. 1.

   Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology. 1970;18:723-37.

   Not in our library

2. 2.

   Gershon RK, Kondo K. Infectious immunological tolerance. Immunology. 1971;21:903-14.

   Not in our library

3. 3.

   Gershon RK, Cohen P, Hencin R, Liebhaber SA. Suppressor T cells. J Immunol. 1972;108:586-90.

   Not in our library

4. 4.

   Moller G. Do suppressor T cells exist? Scand J Immunol. 1988;27:247-50.

   Not in our library10.1111/j.1365-3083.1988.tb02344.x

5. 5.

   Sakaguchi S, Wing K, Miyara M. Regulatory T cells – a brief history and perspective. Eur J Immunol. 2007;37(Suppl. 1):S116-23.

   Not in our library10.1002/eji.200737593

6. 6.

   Sojka DK, Huang YH, Fowell DJ. Mechanisms of regulatory T-cell suppression – a diverse arsenal for a moving target. Immunology. 2008;124:13-22.

   Not in our library10.1111/j.1365-2567.2008.02813.x

7. 7.

   Tang Q, Bluestone JA. The Foxp3 + regulatory T cell: a jack of all trades, master of regulation. Nat Immun. 2008;9:239-44.

   Not in our library10.1038/ni1572

8. 8.

   Stockinger B, Barthlott T, Kassiotis G. T cell regulation: a special job or everyone’s responsibility? Nat Immun. 2001;2:757-8.

   Not in our library10.1038/ni0901-757

9. 9.

   Zinkernagel RM. On cross-priming of MHC class I-specific CTL: rule or exception? Eur J Immunol. 2002;32:2385-92.

   Not in our library10.1002/1521-4141(200209)32:9<2385::aid-immu2385>3.0.co;2-v

10. 10.

    Alpan O, Bachelder E, Isil E, Arnheiter H, Matzinger P. ‘Educated’ dendritic cells act as messengers from memory to naive T helper cells. Nat Immun. 2004;5:615-22.

    Not in our library10.1038/ni1077

11. 11.

    Matzinger P. Friendly and dangerous signals: is the tissue in control? Nat Immun. 2007;8:11-3.

    Not in our library10.1038/ni0107-11

12. 12.

    Jankovic D, Kullberg MC, Feng CG, et al. Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J Exp Med. 2007;204:273-83.

    Not in our library10.1084/jem.20062175

13. 13.

    Cohn M. What roles do regulatory T cells play in the control of the adaptive immune response? Int Immunol. 2008;20:1107-18.

    Not in our library10.1093/intimm/dxn088

14. 14.

    Dembic Z. Beginning of the end of (understanding) the immune response. Scand J Immunol. 2008;68:381-2.

    Not in our library10.1111/j.1365-3083.2008.02159.x

15. 15.

    Cohn M. A reply to Dembic: on an end to the beginning of misunderstanding the immune response. Scand J Immunol. 2009;69:302-5.

    Not in our library10.1111/j.1365-3083.2009.02230.x

16. 16.

    Anderson CC. Placing regulatory T cells into global theories of immunity: an analysis of Cohn’s challenge to integrity (Dembic). Scand J Immunol. 2009;69:306-9.

    Not in our library10.1111/j.1365-3083.2009.02238.x

17. 17.

    Cohn M. On the critique by Colin Anderson of “A Reply to Dembic: On an end to the beginning of mis-understanding the immune response”. Scand J Immunol. 2009;70:1-9.

    Not in our library10.1111/j.1365-3083.2009.02264.x

18. 18.

    Anderson CC. On the sorting of the repertoire: An analysis of Cohn’s challenge to integrity (Dembic), round 2. Scand J Immunol. 2009.

    Not in our library10.1111/j.1365-3083.2009.02288.x

19. 19.

    Cohn M. A rationalized set of default postulates that permit a coherent description of the immune system amenable to computer modeling. Scand J Immunol. 2008;68:371-80.

    Not in our library10.1111/j.1365-3083.2008.02158.x

20. 20.

    Cunliffe J. Intentional pathogen killing – or denial of substrate? Scand J Immunol. 2007;66:604-9.

    Not in our library10.1111/j.1365-3083.2007.02017.x

21. 21.

    Nagy ZA. Evolutionary origin of the immune system: a dialogue with Rod Langman. Scand J Immunol. 2008;67:313-21.

    Not in our library10.1111/j.1365-3083.2008.02075.x

22. 22.

    Cunliffe J. A proliferation of pathogens through the 20th century. Scand J Immunol. 2008;68:120-8.

    Not in our library10.1111/j.1365-3083.2008.02130.x

23. 23.

    McGonagle D, Georgouli T. The importance of ‘Mechnikov’s thorn’ for an improved understanding of 21st century medicine and immunology: a view from the eye. Scand J Immunol. 2008;68:129-39.

    Not in our library10.1111/j.1365-3083.2008.02114.x

24. 24.

    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;155:1151-64.

    Not in our library

25. 25.

    Wang R, Song L, Han G, et al. Mechanisms of regulatory T-cell induction by antigen-IgG-transduced splenocytes. Scand J Immunol. 2007;66:515-22.

    Not in our library10.1111/j.1365-3083.2007.02004.x

26. 26.

    Piao WH, Jee YH, Liu RL, et al. IL-21 modulates CD4 + CD25 + regulatory T-cell homeostasis in experimental autoimmune encephalomyelitis. Scand J Immunol. 2008;67:37-46.

    Not in our library10.1111/j.1365-3083.2007.02035.x

27. 27.

    Wang Y, Meng J, Wang X, et al. Expression of human TIM-1 and TIM-3 on lymphocytes from systemic lupus erythematosus patients. Scand J Immunol. 2008;67:63-70.

    Not in our library10.1111/j.1365-3083.2007.02038.x

28. 28.

    Curotto de Lafaille MA, Muriglan S, Sunshine MJ, et al. Hyper immunoglobulin E response in mice with monoclonal populations of B and T lymphocytes. J Exp Med. 2001;194:1349-59.

    Not in our library10.1084/jem.194.9.1349

29. 29.

    Akbari O, Freeman GJ, Meyer EH, et al. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med. 2002;8:1024-32.

    Not in our library10.1038/nm745

30. 30.

    Zuany-Amorim C, Sawicka E, Manlius C, et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med. 2002;8:625-9.

    Not in our library10.1038/nm0602-625

31. 31.

    Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science. 1994;265:1237-40.

    Not in our library10.1126/science.7520605

32. 32.

    Weiner HL. Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today. 1997;18:335-43.

    Not in our library10.1016/s0167-5699(97)01053-0

33. 33.

    Zhang X, Izikson L, Liu L, Weiner HL. Activation of CD25(+)CD4(+) regulatory T cells by oral antigen administration. J Immunol. 2001;167:4245-53.

    Not in our library10.4049/jimmunol.167.8.4245

34. 34.

    Karlsson MR, Rugtveit J, Brandtzaeg P. Allergen-responsive CD4 + CD25 + regulatory T cells in children who have outgrown cow’s milk allergy. J Exp Med. 2004;199:1679-88.

    Not in our library10.1084/jem.20032121

35. 35.

    Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immun. 2004;5:266-71.

    Not in our library10.1038/ni1037

36. 36.

    Asseman C, Fowler S, Powrie F. Control of experimental inflammatory bowel disease by regulatory T cells. Am J Respir Crit Care Med. 2000;162:S185-9.

    Not in our library10.1164/ajrccm.162.supplement_3.15tac9

37. 37.

    Hori S, Carvalho TL, Demengeot J. CD25 + CD4 + regulatory T cells suppress CD4 + T cell-mediated pulmonary hyperinflammation driven by Pneumocystis carinii in immunodeficient mice. Eur J Immunol. 2002;32:1282-91.

    Not in our library10.1002/1521-4141(200205)32:5<1282::aid-immu1282>3.0.co;2-#

38. 38.

    Kullberg MC, Jankovic D, Gorelick PL, et al. Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis. J Exp Med. 2002;196:505-15.

    Not in our library10.1084/jem.20020556

39. 39.

    Baecher-Allan C, Viglietta V, Hafler DA. Inhibition of human CD4(+)CD25(+high) regulatory T cell function. J Immunol. 2002;169:6210-7.

    Not in our library10.4049/jimmunol.169.11.6210

40. 40.

    Oldenhove G, de Heusch M, Urbain-Vansanten G, et al. CD4 + CD25 + regulatory T cells control T helper cell type 1 responses to foreign antigens induced by mature dendritic cells in vivo. J Exp Med. 2003;198:259-66.

    Not in our library10.1084/jem.20030654

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