Antigen-specific regulatory T-cell responses to intestinal microbiota

Mucosal Immunology

Volumn 10, Issue 6, 2017, Pages 1375-1386

  Russler Germain, E V ^a   Rengarajan, S ^a   Hsieh, C S ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

IMMUNOGLOBULIN A; BACTERIAL ANTIGEN; T LYMPHOCYTE RECEPTOR;

ADAPTIVE IMMUNITY; ANTIGEN SPECIFICITY; B LYMPHOCYTE; CELL DIFFERENTIATION; CELLULAR IMMUNITY; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; IMMUNOREGULATION; INTESTINE FLORA; LYMPHOCYTE SUBPOPULATION; NONHUMAN; PRIORITY JOURNAL; REVIEW; SPECIES DIFFERENCE; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; ANIMAL; COLON; HOMEOSTASIS; IMMUNOLOGY; METABOLISM; MICROBIOLOGY; REGULATORY T LYMPHOCYTE; SYMBIOSIS;

ANIMALS; ANTIGENS, BACTERIAL; B-LYMPHOCYTES; COLON; GASTROINTESTINAL MICROBIOME; HOMEOSTASIS; HUMANS; IMMUNITY, CELLULAR; IMMUNOGLOBULIN A; SYMBIOSIS; T-CELL ANTIGEN RECEPTOR SPECIFICITY; T-LYMPHOCYTES, REGULATORY;

EID: 85031743617     PISSN: 19330219     EISSN: 19353456     Source Type: Journal    
DOI: 10.1038/mi.2017.65     Document Type: Review

References (131)

1. Gilbert, J.A. et al. Microbiome-wide association studies link dynamic microbial consortia to disease. Nature 535, 94-103 (2016).
2. Hand, T.W. The role of the microbiota in shaping infectious immunity. Trends Immunol. 37, 647-658 (2016).
3. Leslie, J.L. & Young, V.B. The rest of the story: the microbiome and gastrointestinal infections. Curr. Opin. Microbiol. 23, 121-125 (2015).
4. Flint, H.J., Scott, K.P., Louis, P. & Duncan, S.H. The role of the gut microbiota in nutrition and health. Nat. Rev. Gastroenterol. Hepatol. 9, 577-589 (2012).
5. Blanton, L.V., Barratt, M.J., Charbonneau, M.R., Ahmed, T. & Gordon, J.I. Childhood undernutrition, the gut microbiota, and microbiota-directed therapeutics. Science 352, 1533 (2016).
6. Belkaid, Y. Regulatory T cells and infection: a dangerous necessity. Nat. Rev. Immunol. 7, 875-888 (2007).
7. Maizels, R.M. & Smith, K.A. Regulatory Tcells in infection. Adv. Immunol. 112, 73-136 (2011).
8. Maloy, K.J. & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298-306 (2011).
9. Alexander, K.L., Targan, S.R. & Elson, C.O. 3rd Microbiota activation and regulation of innate and adaptive immunity. Immunol. Rev. 260, 206-220 (2014).
10. Honda, K. & Littman, D.R. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75-84 (2016).
11. Mombaerts, P.,Mizoguchi, E., Grusby, M.J., Glimcher, L.H., Bhan, A.K. & Tonegawa, S. Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell 75, 274-282 (1993).
12. Veazey, R.S. et al. Gastrointestinal tract as a major site of CD4 T cell depletion and viral replication in SIV infection. Science 280, 427-431 (1998).
13. Brenchley, J.M. & Douek, D.C. HIV infection and the gastrointestinal immune system. Mucosal Immunol. 1, 23-30 (2008).
14. Vallance, B.A., Deng,W., Knodler, L.A. & Finlay, B.B.Mice lacking Tand B lymphocytes develop transient colitis and crypt hyperplasia yet suffer impaired bacterial clearance during Citrobacter rodentium infection. Infect. Immun. 70, 2070-2081 (2002).
15. Simmons, C.P. et al. Central role for B lymphocytes and CD4 T cells in immunity to infection by the attaching and effacing pathogen Citrobacter rodentium. Infect. Immun. 71, 5077-5086 (2003).
16. Maloy, K.J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nat. Immunol. 2, 816-822 (2001).
17. Josefowicz, S.Z., Lu, L.F. & Rudensky, A.Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531-564 (2012).
18. Roncarolo, M.G., Gregori, S., Bacchetta, R. & Battaglia, M. Tr1 cells and the counter-regulation of immunity: natural mechanisms and therapeutic applications. Curr. Top. Microbiol. Immunol. 380, 39-68 (2014).
19. Sun, M., He, C., Cong, Y. & Liu, Z. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota. Mucosal Immunol. 8, 969-978 (2015).
20. Sarrabayrouse, G., Alameddine, J., Altare, F. & Jotereau, F. Microbiotaspecific CD4CD8alphaalpha tregs role in intestinal immune homeostasis and implications for IBD. Front. Immunol. 6, 522 (2015).
21. Sujino, T. et al. Tissue adaptation of regulatory and intraepithelial CD4() T cells controls gut inflammation. Science 352, 1581-1586 (2016).
22. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337-341 (2011).
23. Geuking, M.B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794-806 (2011).
24. Klein, L., Kyewski, B., Allen, P.M. & Hogquist, K.A. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat. Rev. Immunol. 14, 377-391 (2014).
25. Lee, H.M., Bautista, J.L., Scott-Browne, J., Mohan, J.F. & Hsieh, C.S. A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity 37, 475-486 (2012).
26. Cebula, A. et al. Thymus-derived regulatory Tcells contribute to tolerance to commensal microbiota. Nature 497, 258-262 (2013).
27. Thornton, A.M. et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3 T regulatory cells. J. Immunol. 184, 3433-3441 (2010).
28. Weiss, J.M. et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3 T reg cells. J. Exp. Med. 209, S1721 (2012).
29. Yadav, M. et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J. Exp. Med. 209, S1711-S1719 (2012).
30. Akimova, T., Beier, U.H.,Wang, L., Levine, M.H. & Hancock,W.W. Helios expression is a marker of T cell activation and proliferation. PLoS ONE 6, e24226 (2011).
31. Gottschalk, R.A., Corse, E. & Allison, J.P. Expression of Helios in peripherally induced Foxp3 regulatory T cells. J. Immunol. 188, 976-980 (2012).
32. Szurek, E. et al. Differences in expression level of helios and neuropilin-1 do not distinguish thymus-derived from extrathymically-induced CD4 Foxp3 regulatory T cells. PLoS ONE 10, e0141161 (2015).
33. Nutsch, K. et al. Rapid and efficient generation of regulatory T cells to commensal antigens in the periphery. Cell Rep. 17, 206-220 (2016).
34. Josefowicz, S.Z. et al. Extrathymically generated regulatory Tcells control mucosal TH2 inflammation. Nature 482, 395-399 (2012).
35. Zheng, Y., Josefowicz, S., Chaudhry, A., Peng, X.P., Forbush, K. & Rudensky,A.Y.Role of conserved non-codingDNAelements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808-812 (2010).
36. Lathrop, S.K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250-254 (2011).
37. Stadinski, B.D. et al. Hydrophobic CDR3 residues promote the development of self-reactive T cells. Nat. Immunol. 17, 946-955 (2016).
38. Haribhai, D. et al. A central role for induced regulatory Tcells in tolerance induction in experimental colitis. J. Immunol. 182, 3461-3468 (2009).
39. Haribhai, D. et al. A requisite role for induced regulatory Tcells in tolerance based on expanding antigen receptor diversity. Immunity 35, 109-122 (2011).
40. Legoux, F.P. et al. CD4 Tcell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion. Immunity 43, 896-908 (2015).
41. Burzyn, D. et al. A special population of regulatory T cells potentiates muscle repair. Cell 155, 1282-1295 (2013).
42. Gottschalk, R.A., Corse, E. & Allison, J.P. TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J. Exp. Med. 207, 1701-1711 (2010).
43. Kretschmer, K.,Apostolou, I.,Hawiger, D.,Khazaie,K.,Nussenzweig,M.C. & von Boehmer, H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 6, 1219-1227 (2005).
44. Pantoja-Feliciano, I.G. et al. Biphasic assembly of the murine intestinal microbiota during early development. ISME J. 7, 1112-1115 (2013).
45. Tanoue, T., Atarashi, K. & Honda, K. Development and maintenance of intestinal regulatory T cells. Nat. Rev. Immunol. 16, 295-309 (2016).
46. Chen, W. et al. Conversion of peripheral CD4 CD25-naive T cells to CD4 CD25 regulatory Tcells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 198, 1875-1886 (2003).
47. Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232-236 (2013).
48. Benson, M.J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R.J. All-trans retinoic acid mediates enhanced Treg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765-1774 (2007).
49. Mucida, D. et al. Retinoic acid can directly promote TGF-beta-mediated Foxp3() Treg cell conversion of naive T cells. Immunity 30, 472-473 (2009).
50. Nolting, J. et al. Retinoic acid can enhance conversion of naive into regulatory Tcells independently of secreted cytokines. J. Exp. Med. 206, 2131-2139 (2009).
51. Matteoli, G. et al. Gut CD103 dendritic cells express indoleamine 2,3-dioxygenase which influences Tregulatory/Teffector cell balance and oral tolerance induction. Gut 59, 595-604 (2010).
52. Munn, D.H. & Mellor, A.L. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 34, 137-143 (2013).
53. Smith, P.M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569-573 (2013).
54. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446-450 (2013).
55. Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451-5 (2013).
56. Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128-139 (2014).
57. Chu, H. et al. Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352, 1116-1120 (2016).
58. Ishigame, H., Mosaheb, M.M., Sanjabi, S. & Flavell, R.A. Truncated form of TGF-betaRII, but not its absence, induces memory CD8 T cell expansion and lymphoproliferative disorder in mice. J. Immunol. 190, 6340-6350 (2013).
59. Konkel, J.E. & Chen, W. Balancing acts: the role of TGF-beta in the mucosal immune system. Trends Mol. Med. 17, 668-676 (2011).
60. Feuerer, M., Hill, J.A., Kretschmer, K., von Boehmer, H., Mathis, D. & Benoist, C. Genomic definition of multiple ex vivo regulatory T cell subphenotypes. Proc Natl Acad. Sci. USA 107, 5919-5924 (2010).
61. Xu, L., Kitani, A., Stuelten, C.,McGrady, G., Fuss, I. & Strober,W. Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I. Immunity 33, 313-325 (2010).
62. Tone, Y., Furuuchi, K., Kojima, Y., Tykocinski, M.L., Greene, M.I. & Tone, M. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194-202 (2008).
63. Ramanan, D., Tang, M.S., Bowcutt, R., Loke, P. & Cadwell, K. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus. Immunity 41, 311-324 (2014).
64. Faith, J.J., Ahern, P.P., Ridaura, V.K., Cheng, J. & Gordon, J.I. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci. Transl. Med. 6, 220ra-211 (2014).
65. Yang, Y. et al. Focused specificity of intestinal T17 cells towards commensal bacterial antigens. Nature 510, 152-156 (2014).
66. Hand, T.W. et al. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science 337, 1553-1556 (2012).
67. Pabst, O. & Hornef, M. Gutmicrobiota: a natural adjuvant for vaccination. Immunity 41, 349-351 (2014).
68. Round, J.L. & Mazmanian, S.K. Inducible Foxp3 regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204-12209 (2010).
69. Quintana, F.J. et al. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65-71 (2008).
70. Keubler, L.M., Buettner,M., Hager, C. & Bleich, A. A multihit model: colitis lessons from the interleukin-10-deficient mouse. Inflamm. Bowel Dis. 21, 1967-1975 (2015).
71. Chaudhry, A. et al. Interleukin-10 signaling in regulatory Tcells is required for suppression of Th17 cell-mediated inflammation. Immunity 34, 566-578 (2011).
72. Elson, C.O. & Cong, Y. Host-microbiota interactions in inflammatory bowel disease. Gut Microb. 3, 332-344 (2012).
73. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119-124 (2012).
74. Cummings, R.J. et al. Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs. Nature 539, 565-569 (2016).
75. Wohlfert, E.A. et al. GATA3 controls Foxp3() regulatory Tcell fate during inflammation in mice. J. Clin. Investig. 121, 4503-4515 (2011).
76. Ohnmacht, C. et al. The microbiota regulates type 2 immunity through RORgammat() T cells. Science 349, 989-993 (2015).
77. Sefik, E. et al. Individual intestinal symbionts induce a distinct population of RORgamma() regulatory T cells. Science 349, 993-997 (2015).
78. Yu, F., Sharma, S., Edwards, J., Feigenbaum, L. & Zhu, J. Dynamic expression of transcription factors T-bet and GATA-3 by regulatory Tcells maintains immunotolerance. Nat. Immunol. 16, 197-206 (2015).
79. Solomon, B.D. & Hsieh, C.S. Antigen-specific development of mucosal Foxp3RORgammat T cells from regulatory T cell precursors. J. Immunol. 197, 3512-3519 (2016).
80. Yang, B.H. et al. Foxp3() T cells expressing RORgammat represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol. 9, 444-457 (2016).
81. Ivanov, II et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17 T helper cells. Cell 126, 1121-1133 (2006).
82. Wing, K. et al. CTLA-4 control over Foxp3 regulatory T cell function. Science 322, 271-275 (2008).
83. Esensten, J.H., Helou, Y.A., Chopra, G., Weiss, A. & Bluestone, J.A. CD28 costimulation: from mechanism to therapy. Immunity 44, 973-988 (2016).
84. Qureshi, O.S. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600-603 (2011).
85. Scalapino, K.J. & Daikh, D.I. CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol. Rev. 223, 143-155 (2008).
86. Travis, M.A. & Sheppard,D. TGF-beta activation and function in immunity. Annu. Rev. Immunol. 32, 51-82 (2014).
87. Li, M.O., Wan, Y.Y. & Flavell, R.A. T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1-and Th17-cell differentiation. Immunity 26, 579-591 (2007).
88. Gutcher, I., Donkor, M.K., Ma, Q., Rudensky, A.Y., Flavell, R.A. & Li, M.O. Autocrine transforming growth factor-beta1 promotes in vivo Th17 cell differentiation. Immunity 34, 396-408 (2011).
89. Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40, 1319-1323 (2008).
90. Engelhardt, K.R. et al. Clinical outcome in IL-10-and IL-10 receptordeficient patients with or without hematopoietic stem cell transplantation. J. Allergy Clin. Immunol. 131, 825-830 (2013).
91. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller,W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263-274 (1993).
92. Roers, A. et al. Tcell-specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation. J. Exp. Med. 200, 1289-1297 (2004).
93. Rubtsov, Y.P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546-558 (2008).
94. Maynard, C.L. et al. Regulatory T cells expressing interleukin 10 develop from Foxp3() and Foxp3(-) precursor cells in the absence of interleukin 10. Nat. Immunol. 8, 931-941 (2007).
95. Liu, Z., Gerner, M.Y., Van Panhuys, N., Levine, A.G., Rudensky, A.Y. & Germain, R.N. Immune homeostasis enforced by co-localized effector and regulatory T cells. Nature 528, 225-230 (2015).
96. Macpherson, A.J., McCoy, K.D., Johansen, F.E. & Brandtzaeg, P. The immune geography of IgA induction and function. Mucosal Immunol. 1, 11-22 (2008).
97. Pabst, O. New concepts in the generation and functions of IgA. Nat. Rev. Immunol. 12, 821-832 (2012).
98. Fagarasan, S., Kawamoto, S., Kanagawa, O. & Suzuki, K. Adaptive immune regulation in the gut: Tcell-dependent and Tcell-independent IgA synthesis. Annu. Rev. Immunol. 28, 243-273 (2010).
99. Macpherson, A.J., Gatto, D., Sainsbury, E., Harriman, G.R., Hengartner, H. & Zinkernagel, R.M. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222-2226 (2000).
100. Bemark, M., Boysen, P. & Lycke, N.Y. Induction of gut IgA production through T cell-dependent and T cell-independent pathways. Ann. N. Y. Acad. Sci. 1247, 97-116 (2012).
101. Lindner, C. et al. Age, microbiota, and T cells shape diverse individual IgA repertoires in the intestine. J. Exp. Med. 209, 365-377 (2012).
102. Bunker, J.J. et al. Innate and adaptive humoral responses coat distinct commensal bacteria with immunoglobulin A. Immunity 43, 541-553 (2015).
103. Palm, N.W. et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158, 1000-1010 (2014).
104. Tang, C. et al. Inhibition of dectin-1 Signaling ameliorates colitis by inducing lactobacillus-mediated regulatory T cell expansion in the intestine. Cell Host Microbe 18, 183-197 (2015).
105. Kullberg, M.C. et al. Helicobacter hepaticus triggers colitis in specificpathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12-and gamma interferon-dependent mechanism. Infect. Immun. 66, 5157-5166 (1998).
106. Stepankova,R. et al. Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4 T cells. Inflamm. Bowel Dis. 13, 1202-1211 (2007).
107. Ivanov, II et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485-498 (2009).
108. Robertson, B.R. et al. Mucispirillumschaedleri gen. nov., sp. nov., a spiralshaped bacteriumcolonizing themucus layer of the gastrointestinal tract of laboratory rodents. Int. J. Syst. Evol. Microbiol. 55 (Pt 3), 1199-1204 (2005).
109. Kau, A.L. et al. Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy. Sci. Transl. Med. 7, 276ra-224 (2015).
110. Hirota, K. et al. Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses. Nat. Immunol. 14, 372-379 (2013).
111. Cong, Y., Feng, T., Fujihashi, K., Schoeb, T.R. & Elson, C.O. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc. Natl Acad. Sci. USA 106, 19256-19261 (2009).
112. Karimi, K., Inman, M.D., Bienenstock, J. & Forsythe, P. Lactobacillus reuteri-induced regulatory T cells protect against an allergic airway response in mice. Am. J. Respir. Crit. Care Med. 179, 186-193 (2009).
113. Peterson, D.A.,McNulty,N.P., Guruge, J.L. & Gordon, J.I. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2, 328-339 (2007).
114. Kawamoto, S. et al. Foxp3() Tcells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 41, 152-165 (2014).
115. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3 Tcells in gut Peyer's patches. Science 323, 1488-1492 (2009).
116. Komatsu, N., Mariotti-Ferrandiz, M.E., Wang, Y., Malissen, B., Waldmann, H. & Hori, S. Heterogeneity of natural Foxp3 Tcells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl Acad. Sci. USA 106, 1903-1908 (2009).
117. Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983-988 (2011).
118. Linterman, M.A. et al. Foxp3 follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975-982 (2011).
119. Wollenberg, I. et al. Regulation of the germinal center reaction by Foxp3 follicular regulatory T cells. J. Immunol. 187, 4553-4560 (2011).
120. Thorstenson, K.M. & Khoruts, A. Generation of anergic and potentially immunoregulatory CD25CD4 Tcells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J. Immunol. 167, 188-195 (2001).
121. Zhang, X., Izikson, L., Liu, L. & Weiner, H.L. Activation of CD25() CD4() regulatory Tcells by oral antigen administration. J. Immunol. 167, 4245-4253 (2001).
122. Kim, K.S. et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 351, 858-863 (2016).
123. Hickey, C.A. et al. Colitogenic bacteroides thetaiotaomicron antigens access host immune cells in a sulfatase-dependent manner via outer membrane vesicles. Cell Host Microbe 17, 672-680 (2015).
124. Veenbergen, S. et al. Colonic tolerance develops in the iliac lymph nodes and can be established independent of CD103 dendritic cells. Mucosal Immunol. 9, 894-906 (2015).
125. Shale, M., Schiering, C. & Powrie, F. CD4() T-cell subsets in intestinal inflammation. Immunol. Rev. 252, 164-182 (2013).
126. Kieper,W.C. et al. Recent immune status determines the source of antigens that drive homeostatic Tcell expansion. J. Immunol. 174, 3158-3163 (2005).
127. Kim, J.M., Rasmussen, J.P. & Rudensky, A.Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191-197 (2007).
128. Belkaid, Y., Piccirillo, C.A., Mendez, S., Shevach, E.M. & Sacks, D.L. CD4 CD25 regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502-507 (2002).
129. Hill, J.A. et al. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4CD44hi Cells. Immunity 29, 758-770 (2008).
130. Worbs, T., Hammerschmidt, S.I. & Forster, R. Dendritic cell migration in health and disease. Nat. Rev. Immunol. 17, 30-48 (2017).
131. Knoop, K.A.,Miller,M.J. & Newberry, R.D. Transepithelial antigen delivery in the small intestine: different paths, different outcomes. Curr. Opin. Gastroenterol. 29, 112-118 (2013).