Signals and pathways controlling regulatory T cells

Immunological Reviews

Volumn 258, Issue 1, 2014, Pages 117-131

  Huynh, Alexandria ^a,b   Zhang, Ruan ^b   Turka, Laurence A ^b  

^a HARVARD MEDICAL SCHOOL   (United States)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

T cells; Tolerance suppression anergy; Transplantation

Indexed keywords

CD28 ANTIGEN; ESTROGEN RELATED RECEPTOR ALPHA; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR; MAMMALIAN TARGET OF RAPAMYCIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; T LYMPHOCYTE RECEPTOR;

CELL METABOLISM; CYTOKINE PRODUCTION; GRAFT RECIPIENT; HOMEOSTASIS; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; IN VITRO STUDY; IN VIVO STUDY; LYMPHOCYTE PROLIFERATION; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE ACTIVATION; ANIMAL; GRAFT REJECTION; GRAFT SURVIVAL; IMMUNOLOGY; METABOLISM; ORGAN TRANSPLANTATION; SIGNAL TRANSDUCTION; TRANSPLANTATION TOLERANCE; TREATMENT OUTCOME;

ANIMALS; GRAFT REJECTION; GRAFT SURVIVAL; HUMANS; ORGAN TRANSPLANTATION; SIGNAL TRANSDUCTION; T-LYMPHOCYTES, REGULATORY; TRANSPLANTATION TOLERANCE; TREATMENT OUTCOME;

EID: 84893576757     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12148     Document Type: Review

References (189)

1. Sakaguchi S, Sakaguchi N. Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease. J Immunol 1989;142:471-480.
2. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-336.
3. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-1061.
4. Bennett CL, et al. A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA->AAUGAA) leads to the IPEX syndrome. Immunogenetics 2001;53:435-439.
5. Hall BM. Mechanisms maintaining enhancement of allografts. I. Demonstration of a specific suppressor cell. J Exp Med 1985;161:123-133.
6. Bestard O, et al. Intragraft regulatory T cells in protocol biopsies retain foxp3 demethylation and are protective biomarkers for kidney graft outcome. Am J Transplant 2011;11:2162-2172.
7. Graca L, Cobbold SP, Waldmann H. Identification of regulatory T cells in tolerated allografts. J Exp Med 2002;195:1641-1646.
8. Kendal R, et al. Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance. J Exp Med 2011;208:2043-2053.
9. Kingsley CI, Karim M, Bushell AR, Wood KJ. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J Immunol 2002;168:1080-1086.
10. Chauhan SK, Saban DR, Lee HK, Dana R. Levels of Foxp3 in regulatory T cells reflect their functional status in transplantation. J Immunol 2009;182:148-153.
11. Kawai M, Kitade H, Mathieu C, Waer M, Pirenne J. Inhibitory and stimulatory effects of cyclosporine A on the development of regulatory T cells in vivo. Transplantation 2005;79:1073-1077.
12. Li Y, et al. The presence of Foxp3 expressing T cells within grafts of tolerant human liver transplant recipients. Transplantation 2008;86:1837-1843.
13. Muthukumar T, et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med 2005;353:2342-2351.
14. Taflin C, et al. Regulatory T cells in kidney allograft infiltrates correlate with initial inflammation and graft function. Transplantation 2010;89:194-199.
15. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 2005;105:4743-4748.
16. Battaglia M, et al. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 2006;177:8338-8347.
17. Hester J, Schiopu A, Nadig SN, Wood KJ. Low-dose rapamycin treatment increases the ability of human regulatory T cells to inhibit transplant arteriosclerosis in vivo. Am J Transplant 2012;12:2008-2016.
18. Nikolaeva N, Bemelman FJ, Yong SL, van Lier RA, ten Berge IJ. Rapamycin does not induce anergy but inhibits expansion and differentiation of alloreactive human T cells. Transplantation 2006;81:445-454.
19. Strauss L, Czystowska M, Szajnik M, Mandapathil M, Whiteside TL. Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin. PLoS ONE 2009;4:e5994.
20. Strauss L, et al. Selective survival of naturally occurring human CD4+CD25+Foxp3+ regulatory T cells cultured with rapamycin. J Immunol 2007;178:320-329.
21. Zeiser R, et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood 2008;111:453-462.
22. Bunjes D, Hardt C, Rollinghoff M, Wagner H. Cyclosporin A mediates immunosuppression of primary cytotoxic T cell responses by impairing the release of interleukin 1 and interleukin 2. Eur J Immunol 1981;11:657-661.
23. Li Y, et al. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med 1999;5:1298-1302.
24. O'Keefe SJ, Tamura J, Kincaid RL, Tocci MJ, O'Neill EA. FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature 1992;357:692-694.
25. Coenen JJ, Koenen HJ, van Rijssen E, Hilbrands LB, Joosten I. Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells. Blood 2006;107:1018-1023.
26. Nishizuka Y, Sakakura T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 1969;166:753-755.
27. Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 1996;184:387-396.
28. Fontenot JD, Dooley JL, Farr AG, Rudensky AY. Developmental regulation of Foxp3 expression during ontogeny. J Exp Med 2005;202:901-906.
29. Bensinger SJ, Bandeira A, Jordan MS, Caton AJ, Laufer TM. Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immunoregulatory T cells. J Exp Med 2001;194:427-438.
30. Tai X, Cowan M, Feigenbaum L, Singer A. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol 2005;6:152-162.
31. Pennington DJ, et al. Early events in the thymus affect the balance of effector and regulatory T cells. Nature 2006;444:1073-1077.
32. Hsieh CS, Lee HM, Lio CW. Selection of regulatory T cells in the thymus. Nat Rev Immunol 2012;12:157-167.
33. Itoh M, et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 1999;162:5317-5326.
34. Hori S, Haury M, Coutinho A, Demengeot J. Specificity requirements for selection and effector functions of CD25+4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice. Proc Natl Acad Sci USA 2002;99:8213-8218.
35. Jordan MS, et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol 2001;2:301-306.
36. Koonpaew S, Shen S, Flowers L, Zhang W. LAT-mediated signaling in CD4+CD25+ regulatory T cell development. J Exp Med 2006;203:119-129.
37. Shen S, et al. The importance of LAT in the activation, homeostasis, and regulatory function of T cells. J Biol Chem 2010;285:35393-35405.
38. Chuck MI, Zhu M, Shen S, Zhang W. The role of the LAT-PLC-gamma1 interaction in T regulatory cell function. J Immunol 2010;184:2476-2486.
39. Siggs OM, et al. Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions. Immunity 2007;27:912-926.
40. Hsu LY, Tan YX, Xiao Z, Malissen M, Weiss A. A hypomorphic allele of ZAP-70 reveals a distinct thymic threshold for autoimmune disease versus autoimmune reactivity. J Exp Med 2009;206:2527-2541.
41. Tanaka S, et al. Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function. J Immunol 2010;185:2295-2305.
42. Gupta S, et al. Differential requirement of PKC-theta in the development and function of natural regulatory T cells. Mol Immunol 2008;46:213-224.
43. Schmidt-Supprian M, et al. Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-kappaB activation. Proc Natl Acad Sci USA 2004;101:4566-4571.
44. Barnes MJ, et al. Commitment to the regulatory T cell lineage requires CARMA1 in the thymus but not in the periphery. PLoS Biol 2009;7:e51.
45. Molinero LL, et al. CARMA1 controls an early checkpoint in the thymic development of FoxP3+ regulatory T cells. J Immunol 2009;182:6736-6743.
46. Isomura I, et al. c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J Exp Med 2009;206:3001-3014.
47. Zheng Y, Vig M, Lyons J, Van Parijs L, Beg AA. Combined deficiency of p50 and cRel in CD4+ T cells reveals an essential requirement for nuclear factor kappaB in regulating mature T cell survival and in vivo function. J Exp Med 2003;197:861-874.
48. Schmidt-Supprian M, et al. Mature T cells depend on signaling through the IKK complex. Immunity 2003;19:377-389.
49. Kawahata K, et al. Generation of CD4(+)CD25(+) regulatory T cells from autoreactive T cells simultaneously with their negative selection in the thymus and from nonautoreactive T cells by endogenous TCR expression. J Immunol 2002;168:4399-4405.
50. Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 2006;7:401-410.
51. Moran AE, et al. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J Exp Med 2011;208:1279-1289.
52. Cozzo Picca C, et al. CD4(+)CD25(+)Foxp3(+) regulatory T cell formation requires more specific recognition of a self-peptide than thymocyte deletion. Proc Natl Acad Sci USA 2011;108:14890-14895.
53. Hsieh CS, et al. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 2004;21:267-277.
54. Liu X, et al. T cell receptor CDR3 sequence but not recognition characteristics distinguish autoreactive effector and Foxp3(+) regulatory T cells. Immunity 2009;31:909-920.
55. Pacholczyk R, Ignatowicz H, Kraj P, Ignatowicz L. Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity 2006;25:249-259.
56. van Santen HM, Benoist C, Mathis D. Number of T reg cells that differentiate does not increase upon encounter of agonist ligand on thymic epithelial cells. J Exp Med 2004;200:1221-1230.
57. Walker LS, Chodos A, Eggena M, Dooms H, Abbas AK. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J Exp Med 2003;198:249-258.
58. Fisson S, et al. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J Exp Med 2003;198:737-746.
59. Bhandoola A, et al. Peripheral expression of self-MHC-II influences the reactivity and self-tolerance of mature CD4(+) T cells: evidence from a lymphopenic T cell model. Immunity 2002;17:425-436.
60. Gavin MA, Clarke SR, Negrou E, Gallegos A, Rudensky A. Homeostasis and anergy of CD4(+)CD25(+) suppressor T cells in vivo. Nat Immunol 2002;3:33-41.
61. Kim JK, et al. Impact of the TCR signal on regulatory T cell homeostasis, function, and trafficking. PLoS ONE 2009;4:e6580.
62. Lathrop SK, Santacruz NA, Pham D, Luo J, Hsieh CS. Antigen-specific peripheral shaping of the natural regulatory T cell population. J Exp Med 2008;205:3105-3117.
63. Kretschmer K, et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 2005;6:1219-1227.
64. Thorstenson KM, Khoruts A. Generation of anergic and potentially immunoregulatory CD25+CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J Immunol 2001;167:188-195.
65. Gottschalk RA, Corse E, Allison JP. TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J Exp Med 2010;207:1701-1711.
66. Molinero LL, Miller ML, Evaristo C, Alegre ML. High TCR stimuli prevent induced regulatory T cell differentiation in a NF-kappaB-dependent manner. J Immunol 2011;186:4609-4617.
67. Williams JA, et al. Regulated costimulation in the thymus is critical for T cell development: dysregulated CD28 costimulation can bypass the pre-TCR checkpoint. J Immunol 2005;175:4199-4207.
68. Punt JA, Osborne BA, Takahama Y, Sharrow SO, Singer A. Negative selection of CD4+CD8+ thymocytes by T cell receptor-induced apoptosis requires a costimulatory signal that can be provided by CD28. J Exp Med 1994;179:709-713.
69. Page DM. Cutting edge: thymic selection and autoreactivity are regulated by multiple coreceptors involved in T cell activation. J Immunol 1999;163:3577-3581.
70. Noel PJ, Alegre ML, Reiner SL, Thompson CB. Impaired negative selection in CD28-deficient mice. Cell Immunol 1998;187:131-138.
71. Kishimoto H, et al. Differing roles for B7 and intercellular adhesion molecule-1 in negative selection of thymocytes. J Exp Med 1996;184:531-537.
72. Buhlmann JE, Elkin SK, Sharpe AH. A role for the B7-1/B7-2:CD28/CTLA-4 pathway during negative selection. J Immunol 2003;170:5421-5428.
73. Salomon B, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 2000;12:431-440.
74. Tang Q, et al. Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol 2003;171:3348-3352.
75. Nazarov-Stoica C, Surls J, Bona C, Casares S, Brumeanu TD. CD28 signaling in T regulatory precursors requires p56lck and rafts integrity to stabilize the Foxp3 message. J Immunol 2009;182:102-110.
76. Vang KB, et al. Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. J Immunol 2010;184:4074-4077.
77. Grigoriadis G, et al. c-Rel controls multiple discrete steps in the thymic development of Foxp3+ CD4 regulatory T cells. PLoS ONE 2011;6:e26851.
78. Zheng Y, et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 2010;463:808-812.
79. Lio CW, Dodson LF, Deppong CM, Hsieh CS, Green JM. CD28 facilitates the generation of Foxp3(-) cytokine responsive regulatory T cell precursors. J Immunol 2010;184:6007-6013.
80. Hinterberger M, Wirnsberger G, Klein L. B7/CD28 in central tolerance: costimulation promotes maturation of regulatory T cell precursors and prevents their clonal deletion. Front Immunol 2011;2:30.
81. Lohr J, Knoechel B, Kahn EC, Abbas AK. Role of B7 in T cell tolerance. J Immunol 2004;173:5028-5035.
82. Lohr J, Knoechel B, Jiang S, Sharpe AH, Abbas AK. The inhibitory function of B7 costimulators in T cell responses to foreign and self-antigens. Nat Immunol 2003;4:664-669.
83. Lin CH, Hunig T. Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist. Eur J Immunol 2003;33:626-638.
84. Beyersdorf N, Balbach K, Hunig T, Kerkau T. Large-scale expansion of rat CD4+ CD25+ T(reg) cells in the absence of T-cell receptor stimulation. Immunology 2006;119:441-450.
85. Beyersdorf N, et al. Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis. J Exp Med 2005;202:445-455.
86. Zhang R, et al. An obligate cell-intrinsic function for CD28 in Tregs. J Clin Invest 2013;123:580-593.
87. Liang S, et al. Conversion of CD4+ CD25- cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J Exp Med 2005;201:127-137.
88. Hombach AA, Kofler D, Hombach A, Rappl G, Abken H. Effective proliferation of human regulatory T cells requires a strong costimulatory CD28 signal that cannot be substituted by IL-2. J Immunol 2007;179:7924-7931.
89. Golovina TN, et al. CD28 costimulation is essential for human T regulatory expansion and function. J Immunol 2008;181:2855-2868.
90. Moriggl R, et al. Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 1999;10:249-259.
91. Sadlack B, et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 1993;75:253-261.
92. Willerford DM, et al. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 1995;3:521-530.
93. Almeida AR, Legrand N, Papiernik M, Freitas AA. Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J Immunol 2002;169:4850-4860.
94. Wolf M, Schimpl A, Hunig T. Control of T cell hyperactivation in IL-2-deficient mice by CD4(+)CD25(-) and CD4(+)CD25(+) T cells: evidence for two distinct regulatory mechanisms. Eur J Immunol 2001;31:1637-1645.
95. Bayer AL, Yu A, Adeegbe D, Malek TR. Essential role for interleukin-2 for CD4(+)CD25(+) T regulatory cell development during the neonatal period. J Exp Med 2005;201:769-777.
96. Bayer AL, Yu A, Malek TR. Function of the IL-2R for thymic and peripheral CD4+CD25+ Foxp3+ T regulatory cells. J Immunol 2007;178:4062-4071.
97. Curotto de Lafaille MA, Lino AC, Kutchukhidze N, Lafaille JJ. CD25- T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. J Immunol 2004;173:7259-7268.
98. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 2005;201:723-735.
99. D'Cruz LM, Klein L. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 2005;6:1152-1159.
100. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 2005;6:1142-1151.
101. Burchill MA, et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 2008;28:112-121.
102. Lio CW, Hsieh CS. A two-step process for thymic regulatory T cell development. Immunity 2008;28:100-111.
103. Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol 2007;178:280-290.
104. Chen W, et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003;198:1875-1886.
105. Davidson TS, DiPaolo RJ, Andersson J, Shevach EM. Cutting edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J Immunol 2007;178:4022-4026.
106. Yu A, Zhu L, Altman NH, Malek TR. A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity 2009;30:204-217.
107. Komatsu N, et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA 2009;106:1903-1908.
108. Miyao T, et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 2012;36:262-275.
109. Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 2007;445:766-770.
110. Boyman O, Kovar M, Rubinstein MP, Surh CD, Sprent J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 2006;311:1924-1927.
111. Tang Q, et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 2008;28:687-697.
112. Webster KE, et al. In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J Exp Med 2009;206:751-760.
113. Barron L, et al. Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J Immunol 2010;185:6426-6430.
114. Denny P, et al. Mapping of the IDDM locus Idd3 to a 0.35-cM interval containing the interleukin-2 gene. Diabetes 1997;46:695-700.
115. Garg G, et al. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function. J Immunol 2012;188:4644-4653.
116. Goudy K, et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol 2013;146:248-261.
117. Matesanz F, et al. IL2RA/CD25 polymorphisms contribute to multiple sclerosis susceptibility. J Neurol 2007;254:682-684.
118. van Heel DA, et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 2007;39:827-829.
119. Zhernakova A, et al. Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases. Am J Hum Genet 2007;81:1284-1288.
120. Todd JA, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007;39:857-864.
121. Di Cristofano A, et al. Impaired Fas response and autoimmunity in Pten+/- mice. Science 1999;285:2122-2125.
122. Haxhinasto S, Mathis D, Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med 2008;205:565-574.
123. Liu X, et al. Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice. J Clin Invest 2010;120:2497-2507.
124. Ouyang W, et al. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat Immunol 2010;11:618-627.
125. Ouyang W, et al. Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature 2012;491:554-559.
126. Patton DT, et al. Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4+CD25+Foxp3+ regulatory T cells. J Immunol 2006;177:6598-6602.
127. Sauer S, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA 2008;105:7797-7802.
128. Suzuki A, et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 2001;14:523-534.
129. Walsh PT, et al. PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J Clin Invest 2006;116:2521-2531.
130. Franke TF, et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 1995;81:727-736.
131. Pullen N, et al. Phosphorylation and activation of p70s6k by PDK1. Science 1998;279:707-710.
132. Whitman M, Downes CP, Keeler M, Keller T, Cantley L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 1988;332:644-646.
133. Stambolic V, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998;95:29-39.
134. Garcia-Cao I, et al. Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell 2012;149:49-62.
135. Kerdiles YM, et al. Foxo transcription factors control regulatory T cell development and function. Immunity 2010;33:890-904.
136. Bensinger SJ, et al. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 2004;172:5287-5296.
137. Delgoffe GM, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 2009;30:832-844.
138. Zeng H, et al. mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 2013;499:485-490.
139. Wang JW, et al. Influence of SHIP on the NK repertoire and allogeneic bone marrow transplantation. Science 2002;295:2094-2097.
140. Kerr WG, Park MY, Maubert M, Engelman RW. SHIP deficiency causes Crohn's disease-like ileitis. Gut 2011;60:177-188.
141. Collazo MM, Paraiso KH, Park MY, Hazen AL, Kerr WG. Lineage extrinsic and intrinsic control of immunoregulatory cell numbers by SHIP. Eur J Immunol 2012;42:1785-1795.
142. Collazo MM, et al. SHIP limits immunoregulatory capacity in the T-cell compartment. Blood 2009;113:2934-2944.
143. Locke NR, et al. SHIP regulates the reciprocal development of T regulatory and Th17 cells. J Immunol 2009;183:975-983.
144. Tarasenko T, et al. T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses. Proc Natl Acad Sci USA 2007;104:11382-11387.
145. Guo L, et al. Lipid phosphatases identified by screening a mouse phosphatase shRNA library regulate T-cell differentiation and protein kinase B AKT signaling. Proc Natl Acad Sci USA 2013;110:E1849-E1856.
146. Dang EV, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 2011;146:772-784.
147. Michalek RD, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 2011;186:3299-3303.
148. Michalek RD, et al. Estrogen-related receptor-alpha is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci USA 2011;108:18348-18353.
149. Gatza E, et al. Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease. Sci Transl Med 2011;3:67ra68.
150. Zheng Y, et al. A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol 2007;178:2163-2170.
151. Procaccini C, et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 2010;33:929-941.
152. De Rosa V, et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity 2007;26:241-255.
153. Procaccini C, et al. Leptin-induced mTOR activation defines a specific molecular and transcriptional signature controlling CD4+ effector T cell responses. J Immunol 2012;189:2941-2953.
154. Kim JS, et al. Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways. Nat Immunol 2013;14:611-618.
155. Frauwirth KA, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 2002;16:769-777.
156. Jacobs SR, et al. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol 2008;180:4476-4486.
157. Gwinn DM, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214-226.
158. Bian L, et al. Dichloroacetate alleviates development of collagen II-induced arthritis in female DBA/1 mice. Arthritis Res Ther 2009;11:R132.
159. Eleftheriadis T, et al. Dichloroacetate at therapeutic concentration alters glucose metabolism and induces regulatory T-cell differentiation in alloreactive human lymphocytes. J Basic Clin Physiol Pharmacol 2013;24:1-6.
160. Shi LZ, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 2011;208:1367-1376.
161. Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 1994;269:23757-23763.
162. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995;92:5510-5514.
163. Cockman ME, et al. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 2000;275:25733-25741.
164. Ohh M, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000;2:423-427.
165. Sladek R, Bader JA, Giguere V. The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol Cell Biol 1997;17:5400-5409.
166. Sonoda J, et al. Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense. Genes Dev 2007;21:1909-1920.
167. Agata Y, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996;8:765-772.
168. Freeman GJ, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192:1027-1034.
169. Raimondi G, Shufesky WJ, Tokita D, Morelli AE, Thomson AW. Regulated compartmentalization of programmed cell death-1 discriminates CD4+CD25+ resting regulatory T cells from activated T cells. J Immunol 2006;176:2808-2816.
170. Francisco LM, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 2009;206:3015-3029.
171. Brahmer JR, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-2465.
172. Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-2454.
173. Sinclair LV, et al. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat Immunol 2008;9:513-521.
174. Fabre S, et al. FOXO1 regulates L-Selectin and a network of human T cell homing molecules downstream of phosphatidylinositol 3-kinase. J Immunol 2008;181:2980-2989.
175. Liu G, et al. The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR. Nat Immunol 2009;10:769-777.
176. Sawicka E, et al. The sphingosine 1-phosphate receptor agonist FTY720 differentially affects the sequestration of CD4+/CD25+ T-regulatory cells and enhances their functional activity. J Immunol 2005;175:7973-7980.
177. Daniel C, et al. FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells. J Immunol 2007;178:2458-2468.
178. Rubtsov YP, et al. Stability of the regulatory T cell lineage in vivo. Science 2010;329:1667-1671.
179. Zhou X, et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 2009;10:1000-1007.
180. Allan SE, Song-Zhao GX, Abraham T, McMurchy AN, Levings MK. Inducible reprogramming of human T cells into Treg cells by a conditionally active form of FOXP3. Eur J Immunol 2008;38:3282-3289.
181. Delgoffe GM, et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 2013;501:252-256.
182. Hansen W, et al. Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth. J Exp Med 2012;209:2001-2016.
183. Weiss JM, 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 2012;209:1723-1742.
184. Yadav M, et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 2012;209:1713-1722.
185. Hill JA, et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 2007;27:786-800.
186. Polansky JK, et al. DNA methylation controls Foxp3 gene expression. Eur J Immunol 2008;38:1654-1663.
187. Baron U, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol 2007;37:2378-2389.
188. Floess S, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007;5:e38.
189. Lal G, et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol 2009;182:259-273.