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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     Fernandez-Botran R, Sanders VM, Mosmann TR, Vitetta ES. Lymphokine-mediated regulation of the proliferative response of clones of T helper 1 and T helper 2 cells. J Exp Med. 1988;168:543-58.

     Not in our library10.1084/jem.168.2.543

102. 102.

     Swain SL, Weinberg AD, English M, Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990;145:3796-806.

     Not in our library

103. 103.

     Brinkmann V, Geiger T, Alkan S, Heusser CH. Interferon alpha increases the frequency of interferon gamma-producing human CD4 + T cells. J Exp Med. 1993;178:1655-63.

     Not in our library10.1084/jem.178.5.1655

104. 104.

     O’Connor W, Kamanaka M, Booth CJ, et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immun. 2009;10:603-9.

     Not in our library10.1038/ni.1736

105. 105.

     Wurster AL, Rodgers VL, Satoskar AR, et al. Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells. J Exp Med. 2002;196:969-77.

     Not in our library10.1084/jem.20020620

106. 106.

     Yssel H, De Waal Malefyt R, Roncarolo MG, et al. IL-10 is produced by subsets of human CD4 + T cell clones and peripheral blood T cells. J Immunol. 1992;149:2378-84.

     Not in our library

107. 107.

     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;150:353-60.

     Not in our library

108. 108.

     Assenmacher M, Schmitz J, Radbruch A. Flow cytometric determination of cytokines in activated murine T helper lymphocytes: expression of interleukin-10 in interferon-gamma and in interleukin-4-expressing cells. Eur J Immunol. 1994;24:1097-101.

     Not in our library10.1002/eji.1830240513

109. 109.

     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;204:285-97.

     Not in our library10.1084/jem.20061886

110. 110.

     Sun J, Madan R, Karp CL, Braciale TJ. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med. 2009;15:277-84.

     Not in our library10.1038/nm.1929

111. 111.

     Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4 + T cells. J Exp Med. 1996;183:2669-74.

     Not in our library10.1084/jem.183.6.2669

112. 112.

     Coffman RL, Lebman DA, Shrader B. Transforming growth factor beta specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med. 1989;170:1039-44.

     Not in our library10.1084/jem.170.3.1039

113. 113.

     Sonoda E, Matsumoto R, Hitoshi Y, et al. Transforming growth factor beta induces IgA production and acts additively with interleukin 5 for IgA production. J Exp Med. 1989;170:1415-20.

     Not in our library10.1084/jem.170.4.1415

114. 114.

     van Vlasselaer P, Punnonen J, de Vries JE. Transforming growth factor-beta directs IgA switching in human B cells. J Immunol. 1992;148:2062-7.

     Not in our library

115. 115.

     McIntyre TM, Klinman DR, Rothman P, et al. Transforming growth factor beta 1 selectivity stimulates immunoglobulin G2b secretion by lipopolysaccharide-activated murine B cells. J Exp Med. 1993;177:1031-7.

     Not in our library10.1084/jem.177.4.1031

116. 116.

     Satoguina JS, Adjobimey T, Arndts K, et al. Tr1 and naturally occurring regulatory T cells induce IgG4 in B cells through GITR/GITR-L interaction, IL-10 and TGF-beta. Eur J Immunol. 2008;38:3101-13.

     Not in our library10.1002/eji.200838193

117. 117.

     Voo KS, Wang YH, Santori FR, et al. Identification of IL-17-producing FOXP3 + regulatory T cells in humans. Proc Natl Acad Sci U S A. 2009;106:4793-8.

     Not in our library10.1073/pnas.0900408106

118. 118.

     Beriou G, Costantino CM, Ashley CW, et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood. 2009;113:4240-9.

     Not in our library10.1182/blood-2008-10-183251

119. 119.

     Ayyoub M, Deknuydt F, Raimbaud I, et al. 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;106:8635-40.

     Not in our library10.1073/pnas.0900621106

120. 120.

     Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27:68-73.

     Not in our library10.1038/83784

121. 121.

     Wan YY, Flavell RA. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci U S A. 2005;102:5126-31.

     Not in our library10.1073/pnas.0501701102

122. 122.

     Chatila TA, Blaeser F, Ho N, et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest. 2000;106:R75-81.

     Not in our library10.1172/jci11679

123. 123.

     Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27:18-20.

     Not in our library10.1038/83707

124. 124.

     Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27:20-1.

     Not in our library10.1038/83713

125. 125.

     Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3:541-7.

     Not in our library10.1016/1074-7613(95)90125-6

126. 126.

     Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270:985-8.

     Not in our library10.1126/science.270.5238.985

127. 127.

     Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992;359:693-9.

     Not in our library10.1038/359693a0

128. 128.

     Li MO, Sanjabi S, Flavell RA. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity. 2006;25:455-71.

     Not in our library10.1016/j.immuni.2006.07.011

129. 129.

     Hori S. Rethinking the molecular definition of regulatory T cells. Eur J Immunol. 2008;38:928-30.

     Not in our library10.1002/eji.200838147

130. 130.

     Gavin MA, Rasmussen JP, Fontenot JD, et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature. 2007;445:771-5.

     Not in our library10.1038/nature05543

131. 131.

     Lin W, Haribhai D, Relland LM, et al. Regulatory T cell development in the absence of functional Foxp3. Nat Immun. 2007;8:359-68.

     Not in our library10.1038/ni1445

132. 132.

     Hill JA, Feuerer M, Tash K, et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity. 2007;27:786-800.

     Not in our library10.1016/j.immuni.2007.09.010

133. 133.

     Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immun. 2007;8:277-84.

     Not in our library10.1038/ni1437

134. 134.
     Epigenetic Control of the foxp3 Locus in Regulatory T Cells · 2007

     No notice
135. 135.

     Baron U, Floess S, Wieczorek G, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol. 2007;37:2378-89.

     Not in our library10.1002/eji.200737594

136. 136.

     Polansky JK, Kretschmer K, Freyer J, et al. DNA methylation controls Foxp3 gene expression. Eur J Immunol. 2008;38:1654-63.

     Not in our library10.1002/eji.200838105

137. 137.

     Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF. Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem. 2001;276:37672-9.

     Not in our library10.1074/jbc.m104521200

138. 138.

     Marson A, Kretschmer K, Frampton GM, et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature. 2007;445:931-5.

     Not in our library10.1038/nature05478

139. 139.

     Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature. 2007;445:936-40.

     Not in our library10.1038/nature05563

140. 140.

     Chen TC, Cobbold SP, Fairchild PJ, Waldmann H. Generation of anergic and regulatory T cells following prolonged exposure to a harmless antigen. J Immunol. 2004;172:5900-7.

     Not in our library10.4049/jimmunol.172.10.5900

141. 141.

     Groux H, O’Garra A, Bigler M, et al. A CD4 + T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997;389:737-42.

     Not in our library10.1038/39614

142. 142.

     Vieira PL, Christensen JR, Minaee S, et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4 + CD25 + regulatory T cells. J Immunol. 2004;172:5986-93.

     Not in our library10.4049/jimmunol.172.10.5986

143. 143.

     Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG. Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25 + CD4 + Tr cells. Blood. 2005;105:1162-9.

     Not in our library10.1182/blood-2004-03-1211

144. 144.

     Han Y, Guo Q, Zhang M, Chen Z, Cao X. CD69 + CD4 + CD25- T cells, a new subset of regulatory T cells, suppress T cell proliferation through membrane-bound TGF-beta 1. J Immunol. 2009;182:111-20.

     Not in our library10.4049/jimmunol.182.1.111

145. 145.

     Lund JM, Hsing L, Pham TT, Rudensky AY. Coordination of early protective immunity to viral infection by regulatory T cells. Science. 2008;320:1220-4.

     Not in our library10.1126/science.1155209

146. 146.

     Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S. Heterogeneity of natural Foxp3 + T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci U S A. 2009;106:1903-8.

     Not in our library10.1073/pnas.0811556106

147. 147.

     Tsuji M, Komatsu N, Kawamoto S, et al. Preferential generation of follicular B helper T cells from Foxp3 + T cells in gut Peyer’s patches. Science. 2009;323:1488-92.

     Not in our library10.1126/science.1169152

148. 148.

     Duarte JH, Zelenay S, Bergman ML, Martins AC, Demengeot J. Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur J Immunol. 2009;39:948-55.

     Not in our library10.1002/eji.200839196

149. 149.

     Wei G, Wei L, Zhu J, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4 + T cells. Immunity. 2009;30:155-67.

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

150. 150.

     Xu L, Kitani A, Fuss I, Strober W. Cutting edge: regulatory T cells induce CD4 + CD25-Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol. 2007;178:6725-9.

     Not in our library10.4049/jimmunol.178.11.6725

151. 151.

     Yang XO, Nurieva R, Martinez GJ, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity. 2008;29:44-56.

     Not in our library10.1016/j.immuni.2008.05.007

152. 152.

     Zhou L, Lopes JE, Chong MM, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008;453:236-40.

     Not in our library10.1038/nature06878

153. 153.
     DC activated via dectin‐1 convert Treg into IL‐17 producers · 2008

     No notice
154. 154.

     Leon K, Perez R, Lage A, Carneiro J. Modelling T-cell-mediated suppression dependent on interactions in multicellular conjugates. J Theor Biol. 2000;207:231-54.

     Not in our library10.1006/jtbi.2000.2169

155. 155.

     Carneiro J, Leon K, Caramalho I, et al. When three is not a crowd: a Crossregulation model of the dynamics and repertoire selection of regulatory CD4 + T cells. Immunol Rev. 2007;216:48-68.

     Not in our library10.1111/j.1600-065x.2007.00487.x

156. 156.

     Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4 + CD25 + T cell-mediated suppression by dendritic cells. Science. 2003;299:1033-6.

     Not in our library10.1126/science.1078231

157. 157.

     Sutmuller RP, den Brok MH, Kramer M, et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest. 2006;116:485-94.

     Not in our library10.1172/jci25439

158. 158.

     Jonsson R, Ljunggren HG, Natvig JB, Orn A. Goran Moller 1936–2008. Scand J Immunol. 2008;68:113.

     Not in our library10.1111/j.1365-3083.2008.02135.x

159. 159.

     Coutinho A, Holmberg D. Goran Moller 1936–2008. Scand J Immunol. 2008;68:114-7.

     Not in our library10.1111/j.1365-3083.2008.02134.x

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