Quorum-sensing in cD4+t cell homeostasis: A hypothesis and a model

Frontiers in Immunology

Volumn 3, Issue MAY, 2012, Pages

  Almeidal, Afonso R M ^a   Amado, Inês F ^b,c,d   Reynolds, Joseph ^e   Berges, Julien ^b,c,f   Lythe, Grant ^e   Molina París, Carmen ^e   Freitas, Antonio A ^b,c  

^a Institute for Molecular Medicine   (Portugal)

^b INSTITUT PASTEUR   (France)

^c CNRS   (France)

^d UNIVERSITY OF PORTO   (Portugal)

^e UNIVERSITY OF LEEDS   (United Kingdom)

^f SORBONNE UNIVERSITÉ   (France)

Author keywords

Autoimmunity; CD4+ T cells; Homeostasis; IL 2; Immune therapy; Mathematical modeling; Quorum sensing; Regulatory T cells

Indexed keywords

EID: 84871833659     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2012.00125     Document Type: Article

References (117)

1. Almeida, A. R., Borghans, J. A., and Freitas, A. A. (2001). T cell homeostasis: thymus regeneration and peripheral T cell restoration in mice with a reduced fraction of competent precursors. J. Exp. Med. 194, 591-599.
2. + T cell numbers. J. Immunol. 169, 4850-4860.
3. Almeida, A. R., Rocha, B., Freitas, A. A., and Tanchot, C. (2005). Homeostasis of T cell numbers: from thymus production to peripheral compartmentalization and the indexation of regulatory T cells. Semin. Immunol. 17, 239-249.
4. + T cells. Int. Immunol. 18, 1607-1613.
5. + regulatory T cells is indexed to the number of IL-2producing cells. J. Immunol. 177, 192-200.
6. Annacker, O., Burlen-Defranoux, O., Pimenta-Araujo, R., Cumano, A., and Bandeira, A. (2000). Regulatory CD4 T cells control the size of the peripheral activated/memory CD4 T cells compartment. J. Immunol. 164, 3573-3580.
7. + 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. 174, 2591-2601.
8. Asano, M., Toda, M., Sakaguchi, N., and Sakaguchi, S. (1996). Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 184, 387-396.
9. Barthlott, T., Kassiotis, G., and Stockinger, B. (2003). T cell regulation as a side effect of homeostasis and competition. J. Exp. Med. 197, 451-460.
10. Bayer, A. L., Yu, A., Adeegbe, D., and Malek, T. R. (2005). Essential role for interleukin-2 for CD4(+)CD25(+) T regulatory cell development during the neonatal period. J. Exp. Med. 201, 769-777.
11. Belkaid, Y., and Rouse, B. T. (2005). Natural regulatory T cells in infectious disease. Nat. Immunol. 6, 353-360.
12. Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., and Ochs, H. D. (2001). The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20-21.
13. Bernard, C. (1865). Introduction À L'étude de la Médecine Expérimentale. Paris: J.-B. Baillière.
14. Berzins, S. P., Boyd, R. L., and Miller, J. F. (1998). The role of the thymus and recent thymic migrants in the maintenance of the adult peripheral lymphocyte pool. J. Exp. Med. 187, 1839-1848.
15. + CD8T cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse. J. Immunol. 153, 3764-3774.
16. Bocharov, G., Quiel, J., Luzyanina, T., Alon, H., Chiglintsev, E., Chereshnev, V., Meier-Schellersheim, M., Paul, W. E., and Grossman, Z. (2011). Feedback regulation of proliferation vs. differentiation rates explains the dependence of CD4 Tcell expansion on precursor number. Proc. Natl. Acad. Sci. U.S.A. 108, 3318-3323.
17. Boyman, O., Kovar, M., Rubinstein, M. P., Surh, C. D., and Sprent, J. (2006). Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311, 1924-1927.
18. Brocker, T. (1997). Survival of mature CD4 T lymphocytes is dependent on major histocompatibility complex class II-expressing dendritic cells. J. Exp. Med. 186, 1223-1232.
19. + regulatory T cells. J. Immunol. 178, 280-290.
20. Burroughs, N. J., Ferreira, M. F., Oliveira, B., and Pinto, A. A. (2011). Autoimmunity arising from bystander proliferation of T cells in an immune response model. Math. Comput. Model. 53, 1389-1393.
21. Busse, D., De La Rosa, M., Hobiger, K., Thurley, K., Flossdorf, M., Scheffold, A., and Hofer, T. (2010). Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments. Proc. Natl. Acad. Sci. U.S.A. 107, 3058-3063.
22. Cannon, W. (1932). The Wisdom of the Body.NewYork:Norton.
23. + T cells. Immunol. Rev. 216, 48-68.
24. Chaudhry, A., Samstein, R. M., Treuting, P., Liang, Y., Pils, M. C., Heinrich, J. M., Jack, R. S., Wunderlich, F. T., Bruning, J. C., Muller, W., and Rudensky, A. Y. (2011). Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34, 566-578.
25. Chen, Y., Haines, C. J., Gutcher, I., Hochweller, K., Blumenschein, W. M., McClanahan, T., Hammerling, G., Li, M. O., Cua, D. J., and McGeachy, M. J. (2011). Foxp3(+) Regulatory T cells promote T helper 17 cell development in vivo through regulation of interleukin-2. Immunity 34, 409-421.
26. Cobb, B. S., Hertweck, A., Smith, J., O'Connor, E., Graf, D., Cook, T., Smale, S. T., Sakaguchi, S., Livesey, F. J., Fisher, A. G., and Merkenschlager, M. (2006). A role for Dicer in immune regulation. J. Exp. Med. 203, 2519-2527.
27. + regulatory T cells by peripheral expansion. J. Immunol. 173, 7259-7268.
28. de Freitas, A. A. (2009). Tractus Immuno-Logicus: A Brief History of the Immune System. Austin: Landes Bioscience.
29. + regulatory T cell function. Eur. J. Immunol. 34, 2480-2488.
30. Diggle, S. P., Griffin, A. S., Campbell, G. S., and West, S. A. (2007). Cooperation and conflict in quorum-sensing bacterial populations. Nature 450, 411-414.
31. Fehervari, Z., Yamaguchi, T., and Sakaguchi, S. (2006). The dichotomous role of IL-2: tolerance versus immunity. Trends Immunol. 27, 109-111.
32. Feinerman, O., Jentsch, G., Tkach, K. E., Coward, J. W., Hathorn, M. M., Sneddon, M. W., Emonet, T., Smith, K. A., and Altan-Bonnet, G. (2010). Single-cell quantification of IL-2 response by effector and regulatory T cells reveals critical plasticity in immune response. Mol. Syst. Biol. 6, 437.
33. + regulatory T cells. Nat. Immunol. 4, 330-336.
34. Fontenot, J. D., Rasmussen, J. P., Gavin, M. A.,and Rudensky,A.Y. (2005a). A function for interleukin 2 in Foxp3expressing regulatory T cells. Nat. Immunol. 6, 1142-1151.
35. Fontenot, J. D., Rasmussen, J. P., Williams, L. M., Dooley, J. L., Farr, A. G., and Rudensky, A. Y. (2005b). Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329-341.
36. Freitas, A. A., Agenes, F., and Coutinho, G. C. (1996). Cellular competition modulates survival and selection of CD8+ T cells. Eur. J. Immunol. 26, 2640-2649.
37. Freitas, A. A., and Rocha, B. (2000). Population biology of lymphocytes: the flight for survival. Annu. Rev. Immunol. 18, 83-111.
38. Freitas, A. A., and Rocha, B. (2009). Homeostasis of naive T cells: the Foxo that fixes. Nat. Immunol. 10, 133-134.
39. Gavin, M. A., Clarke, S. R., Negrou, E., Gallegos, A., and Rudensky, A. (2002). Homeostasis and energy of CD4(+)CD25(+) suppressor T cells in vivo. Nat. Immunol. 3, 33-41.
40. Goudy, K. S., Johnson, M. C., Garland, A., Li, C., Samulski, R. J., Wang, B., and Tisch, R. (2011). Inducible adeno-associated virusmediated IL-2 gene therapy prevents autoimmune diabetes. J. Immunol. 186, 3779-3786.
41. Gregersen, P. K., and Olsson, L. M. (2009). Recent advances in the genetics of autoimmune disease. Annu. Rev. Immunol. 27, 363-391.
42. Grinberg-Bleyer, Y., Baeyens, A., You, S., Elhage, R., Fourcade, G., Gregoire, S., Cagnard, N., Carpentier, W., Tang, Q., Bluestone, J., Chatenoud, L., Klatzmann, D., Salomon, B. L., and Piaggio, E. (2010). IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J. Exp. Med. 207, 1871-1878.
43. + T cells. Nat. Immunol. 10, 149-157.
44. Hill, J. A., Feuerer, M., Tash, K., Haxhinasto, S., Perez, J., Melamed, R., Mathis, D., and Benoist, C. (2007). Foxp3 transcription-factordependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786-800.
45. Hori, S., Nomura, T., and Sakaguchi, S. (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057-1061.
46. Huang, C. T., Workman, C. J., Flies, D., Pan, X., Marson, A. L., Zhou, G., Hipkiss, E. L., Ravi, S., Kowalski, J., Levitsky, H. I., Powell, J. D., Pardoll, D. M., Drake, C. G., andVignali, D. A. (2004). Role of LAG-3 in regulatory T cells. Immunity 21, 503-513.
47. + T cells in an interleukin-10-dependent manner. Immunity 34, 554-565.
48. + T cells favors terminal-effector differentiation in vivo. Immunity 32, 91-103.
49. Kerdiles, Y. M., Beisner, D. R., Tinoco, R., Dejean, A. S., Castrillon, D. H., Depinho, R. A., and Hedrick, S. M. (2009). Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat. Immunol. 10, 176-184.
50. Khattri, R., Kasprowicz, D., Cox, T., Mortrud, M., Appleby, M. W., Brunkow, M. E., Ziegler, S. F., and Ramsdell, F. (2001). The amount of scurfin protein determines peripheral T cell number and responsiveness. J. Immunol. 167, 6312-6320.
51. Kim, J. M., Rasmussen, J. P., and Rudensky, A. Y. (2007a). Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191-197.
52. Kim, P. S., Lee, P. P., and Levy, D. (2007b). Modeling regulation mechanisms in the immune system. J. Theor. Biol. 246, 33-69.
53. Kirberg, J., Berns, A., and Von Boehmer, H. (1997). Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complexencoded molecules. J. Exp. Med. 186, 1269-1275.
54. Knoechel, B., Lohr, J., Kahn, E., Bluestone, J. A., and Abbas, A. K. (2005). Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J. Exp. Med. 202, 1375-1386.
55. Komatsu, N., Mariotti-Ferrandiz, M. E., Wang, Y., Malissen, B., Waldmann, H., and Hori, S. (2009). Heterogeneity of natural Foxp3+ T cells: a committed regulatory Tcell lineage and an uncommitted minor population retaining plasticity. Proc. Natl. Acad. Sci. U.S.A. 106, 1903-1908.
56. Kundig, T. M., Schorle, H., Bachmann, M. F., Hengartner, H., Zinkernagel, R. M., and Horak, I. (1993). Immune responses in interleukin2-deficient mice. Science 262, 1059-1061.
57. Labrecque, N., Whitfield, L. S., Obst, R., Waltzinger, C., Benoist, C., and Mathis, D. (2001). How much TCR doesaTcellneed?Immunity 15, 71-82.
58. + regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204, 57-63.
59. + T cell survival but not for antigen proliferation. Nat. Immunol. 1, 54-58.
60. Leon, K., Lage, A., and Carneiro, J. (2003). Tolerance and immunity in a mathematical model of T-cell mediated suppression. J. Theor. Biol. 225, 107-126.
61. Leuchars, E., Wallis, V. J., Doenhoff, M. J., Davies,A. J., and Kruger, J. (1978). Studies of hyperthymic mice. I. The influence of multiple thymus grafts on the size of the peripheral T cell pool and immunological performance. Immunology 35, 801-809.
62. Link, A., Vogt, T. K., Favre, S., Britschgi, M. R., Acha-Orbea, H., Hinz, B., Cyster, J. G., and Luther, S. A. (2007). Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255-1265.
63. Liston, A., Lu, L. F., O'Carroll, D., Tarakhovsky, A., and Rudensky, A. Y. (2008). Dicer-dependent microRNA pathway safeguards regulatory T cell function. J. Exp. Med. 205, 1993-2004.
64. Lu, L. F., Thai, T. H., Calado, D. P., Chaudhry, A., Kubo, M., Tanaka, K., Loeb, G. B., Lee, H., Yoshimura, A., Rajewsky, K., and Rudensky, A. Y. (2009). Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 30, 80-91.
65. Malek, T. R. (2008). The biology of interleukin-2. Annu. Rev. Immunol. 26, 453-479.
66. Malek, T. R., and Castro, I. (2010). Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 33, 153-165.
67. Malek, T. R., Porter, B. O., Codias, E. K., Scibelli, P., and Yu, A. (2000). Normal lymphoid homeostasis and lack of lethal autoimmunity in mice containing mature T cells with severely impaired IL-2 receptors. J. Immunol. 164, 2905-2914.
68. Malek, T. R., Yu, A., Vincek, V., Scibelli, P., and Kong, L. (2002). CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167-178.
69. Maloy, K. J., and Powrie, F. (2001). Regulatory T cells in the control of immune pathology. Nat. Immunol. 2, 816-822.
70. Metcalf, D. (1965). Multiple thymus grafts in aged mice. Nature 208, 87-88.
71. Miller, J. F. (1965). Effect of thymectomy in adult mice on immunological responsiveness. Nature 208, 1337-1338.
72. Miller, M. B., and Bassler, B. L. (2001). Quorum sensing in bacteria. Annu. Rev. Microbiol. 55, 165-199.
73. Moriggl, R., Topham, D. J., Teglund, S., Sexl, V., McKay, C., Wang, D., Hoffmeyer,A.,Van Deursen,J.,Sangster, M. Y., Bunting, K. D., Grosveld, G. C., and Ihle, J. N. (1999). Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10, 249-259.
74. Nelson, B. H., and Willerford, D. M. (1998). Biology of the interleukin-2 receptor. Adv. Immunol. 70, 1-81.
75. Ono, M., Yaguchi, H., Ohkura, N., Kitabayashi, I., Nagamura, Y., Nomura, T., Miyachi, Y., Tsukada, T., and Sakaguchi, S. (2007). Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 446, 685-689.
76. Ouyang, W., Beckett, O., Flavell, R. A., and Li, M. O. (2009). An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity 30, 358-371.
77. Pandiyan, P., Conti, H. R., Zheng, L., Peterson, A. C., Mathern, D. R., Hernandez-Santos, N., Edgerton, M., Gaffen, S. L., and Lenardo, M. J. (2011). CD4(+)CD25(+)Foxp3(+) regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 cell infection model. Immunity 34, 422-434.
78. Pipkin,M. E.,Sacks,J. A.,Cruz-Guilloty, F., Lichtenheld, M. G., Bevan, M. J., and Rao, A. (2010). Interleukin2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32, 79-90.
79. Polic, B., Kunkel, D., Scheffold, A., and Rajewsky, K. (2001). How alpha beta T cells deal with induced TCR alpha ablation. Proc. Natl. Acad. Sci. U.S.A. 98, 8744-8749.
80. + T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int. Immunol. 5, 1461-1471.
81. Quiel, J., Caucheteux, S., Laurence, A., Singh, N. J., Bocharov, G., BenSasson,S. Z.,Grossman,Z.,and Paul, W. E. (2011). Antigen-stimulated CD4 T-cell expansion is inversely and log-linearly related to precursor number. Proc. Natl. Acad. Sci. U.S.A. 108, 3312-3317.
82. + T cells. Eur. J. Immunol. 25, 3053-3059.
83. Sakaguchi, S. (2000). Regulatory T cells: key controllers of immunologic selftolerance. Cell 101, 455-458.
84. + regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531-562.
85. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., and Toda, M. (1995). 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. 155, 1151-1164.
86. Sallusto, F., Geginat, J., and Lanzavecchia, A. (2004). Central memory and effector memory T cell subsets: function,generation,and maintenance. Annu. Rev. Immunol. 22, 745-763.
87. Schluns, K. S., Kieper, W. C., Jameson, S. C., and Lefrancois, L. (2000). Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat. Immunol. 1, 426-432.
88. Schorle, H., Holtschke, T., Hunig, T., Schimpl, A., and Horak, I. (1991). Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352, 621-624.
89. Setoguchi, R., Hori, S., Takahashi, T., and Sakaguchi, S. (2005). 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. 201, 723-735.
90. Shevach, E. M. (2000). Regulatory T cells in autoimmmunity. Annu. Rev. Immunol. 18, 423-449.
91. Shevach, E. M. (2009). Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30, 636-645.
92. Snow, J. W., Abraham, N., Ma, M. C., Herndier, B. G., Pastuszak, A. W., and Goldsmith,M.A. (2003). Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5Bdeficient mice. J. Immunol. 171, 5042-5050.
93. Soper, D. M., Kasprowicz, D. J., and Ziegler, S. F. (2007). IL-2Rbeta links IL-2R signaling with Foxp3 expression. Eur. J. Immunol. 37, 1817-1826.
94. + Th cells for TREG mediated suppression. PLoS ONE 4, e7158. doi:10.1371/journal.pone.0007158
95. Surh, C. D., and Sprent, J. (2008). Homeostasis of naive and memory T cells. Immunity 29, 848-862.
96. Suzuki, H., Kundig, T. M., Furlonger, C., Wakeham, A., Timms, E., Matsuyama, T., Schmits, R., Simard, J. J., Ohashi, P. S., Griesser, H., Taniguchi, T., Paige, C. J., and Mak, T. W. (1995). Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 268, 1472-1476.
97. Swain, S. L., Hu, H., and Huston, G. (1999). Class II-independent generation of CD4 memory T cells from effectors. Science 286, 1381-1383.
98. Takeda, K., Tanaka, T., Shi, W., Matsumoto, M., Minami, M., Kashiwamura, S., Nakanishi, K., Yoshida, N., Kishimoto, T., and Akira, S. (1996). Essential role of Stat6 in IL-4 signalling. Nature 380, 627-630.
99. Tan, J. T., Dudl, E., Leroy, E., Murray, R., Sprent, J., Weinberg, K. I., and Surh, C. D. (2001). IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl.Acad. Sci. U.S.A. 98, 8732-8737.
100. Tanchot, C., Lemonnier, F. A., Perarnau, B., Freitas, A. A., and Rocha, B. (1997). Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276, 2057-2062.
101. + T cell pools. Eur. J. Immunol. 25, 2127-2136.
102. Tang, Q., Adams, J. Y., Tooley, A. J., Bi, M., Fife, B. T., Serra, P., Santamaria, P., Locksley, R. M., Krummel, M. F., and Bluestone, J. A. (2006). Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat. Immunol. 7, 83-92.
103. Tang, Q., Adams, J. Y., Penaranda, C., Melli, K., Piaggio, E., Sgouroudis, E., Piccirillo, C. A., Salomon, B. L., and Bluestone, J. A. (2008). Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28, 687-697.
104. Todd, J. A. (2010). Etiology of type 1 diabetes. Immunity 32, 457-467.
105. Vivien, L., Benoist, C., and Mathis, D. (2001). T lymphocytes need IL7 but not IL-4 or IL-6 to survive in vivo. Int. Immunol. 13, 763-768.
106. Webster, K. E., Walters, S., Kohler, R. E., Mrkvan, T., Boyman, O., Surh, C. D., Grey, S. T., and Sprent, J. (2009). In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and longterm acceptance of islet allografts without immunosuppression. J. Exp. Med. 206, 751-760.
107. Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J. L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., Bricarelli, F. D., Byrne, G., McEuen, M., Proll, S., Appleby, M., and Brunkow, M. E. (2001). X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18-20.
108. Willerford, D. M., Chen, J., Ferry, J. A., Davidson, L., Ma, A., and Alt, F. W. (1995). Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521-530.
109. + memory T cells. Nature 441, 890-893.
110. + regulatory T cell function. Science 322, 271-275.
111. Wolf, M., Schimpl, A., and Hunig, T. (2001). 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. 31, 1637-1645.
112. Wu, Y., Borde, M., Heissmeyer, V., Feuerer, M., Lapan, A. D., Stroud, J. C., Bates, D. L., Guo, L., Han, A., Ziegler, S. F., Mathis, D., Benoist, C., Chen, L., and Rao, A. (2006). FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375-387.
113. Yamanouchi, J., Rainbow, D., Serra, P., Howlett, S., Hunter, K., Garner, V. E., Gonzalez-Munoz, A., Clark, J., Veijola, R., Cubbon, R., Chen, S. L., Rosa, R., Cumiskey, A. M., Serreze, D. V., Gregory, S., Rogers, J., Lyons, P. A., Healy, B., Smink, L. J., Todd, J. A., Peterson, L. B., Wicker, L. S., and Santamaria, P. (2007). Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat. Genet. 39, 329-337.
114. Yao,Z.,Kanno,Y.,Kerenyi,M.,Stephens, G., Durant, L., Watford, W. T., Laurence, A., Robinson, G. W., Shevach, E. M., Moriggl, R., Hennighausen, L., Wu, C., and O'Shea, J. J. (2007). Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109, 4368-4375.
115. Yu, A., Zhu, L., Altman, N. H., and Malek, T. R. (2009). A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity 30, 204-217.
116. Zaragoza, B., Evaristo, C., Kissenpfennig, A., Libri, V., Malissen, B., Rocha, B., Freitas, A. A., and Almeida, A. R. (2011). Cell-to-cell interactions and signals involved in the reconstitution of peripheral CD8 T(CM) and T(EM) cell pools. PLoS ONE 6, e17423. doi:10.1371/journal.pone.0017423
117. Zhou, X., Jeker, L. T., Fife, B. T., Zhu, S., Anderson, M. S., McManus, M. T., and Bluestone, J. A. (2008). Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J. Exp. Med. 205, 1983-1991.