IL-2 and IL-15 dependent thymic development of Foxp3-expressing regulatory T lymphocytes
Cécile Apert, Paola Romagnoli, Joost P. M. van Meerwijk
IL-2 and IL-15 dependent thymic development of Foxp3-expressing regulatory T lymphocytes
Immunosuppressive regulatory T lymphocytes (Treg) expressing the transcription factor Foxp3 play a vital role in the maintenance of tolerance of the immunesystem to self and innocuous non-self. Most Treg that are critical for the maintenance of tolerance to self, develop as an independent T-cell lineage from common T cell precursors in the thymus. In this organ, their differentiation requires signals from the T cell receptor for antigen, from co-stimulatory molecules, as well as from cytokine-receptors. Here we focus on the cytokines implicated in thymic development of Treg, with a particular emphasis on the roles of interleukin-2 (IL-2) and IL-15. The more recently appreciated involvement of TGF-β in thymic Treg development is also briefly discussed. Finally, we discuss how cytokine-dependence of Treg development allows for temporal, quantitative, and potentially qualitative modulation of this process.
regulatory T cells / thymus / differentiation / IL-2 / IL-15
[1] |
Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, Rolink A, Klein L (2007) Selection of Foxp3(+) regulatory T cells specific for self antigen expressed and presented by Aire(+) medullary thymic epithelial cells. Nature Immunol 8:351–358
CrossRef
Google scholar
|
[2] |
Bayer AL, Lee JY, de la Barrera A, Surh CD, Malek TR (2008) A function for IL-7R for CD4+CD25+Foxp3+ T regulatory cells. J Immunol 181:225–234
CrossRef
Google scholar
|
[3] |
Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genet 27:20–21
CrossRef
Google scholar
|
[4] |
Bilate AM, Lafaille JJ (2012) Induced CD4+Foxp3+ regulatory Tcells in immune tolerance. Annu Rev Immunol 30:733–758
CrossRef
Google scholar
|
[5] |
Brennecke P, Reyes A, Pinto S, Rattay K, Nguyen M, Kuchler R, Huber W, Kyewski B, Steinmetz LM (2015) Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. Nature Immunol 16:933–941
CrossRef
Google scholar
|
[6] |
Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genetics 27:68–73
CrossRef
Google scholar
|
[7] |
Burchill MA, Goetz CA, Prlic M, O’Neil JJ, Harmon IR, Bensinger SJ, Turka LA, Brennan P, Jameson SC, Farrar MA (2003) Distinct Effects of STAT5 Activation on CD4+ and CD8+ T Cell Homeostasis: Development of CD4+CD25+ Regulatory T Cells versus CD8+ Memory T Cells. J Immunol 171:5853–5864
CrossRef
Google scholar
|
[8] |
Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA (2007) IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol 178:280–290
CrossRef
Google scholar
|
[9] |
Burchill MA, Yang J, Vang KB, Moon JJ, Chu HH, Lio CW, Vegoe AL, Hsieh CS, Jenkins MK, Farrar MA (2008) Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 28:112–121
CrossRef
Google scholar
|
[10] |
Capone M, Romagnoli P, Beermann F, MacDonald HR, van Meerwijk JPM (2001) Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells. Blood 97:1336–1342
CrossRef
Google scholar
|
[11] |
Caramalho I, Nunes-Silva V, Pires AR, Mota C, Pinto AI, Nunes-Cabaco H, Foxall RB, Sousa AE (2015) Human regulatory T-cell development is dictated by Interleukin-2 and-15 expressed in a non-overlapping pattern in the thymus. J Autoimmun 56:98–110
CrossRef
Google scholar
|
[12] |
Castillo EF, Acero LF, Stonier SW, Zhou D, Schluns KS (2010) Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation. Blood 116:2494–2503
CrossRef
Google scholar
|
[13] |
Cebula A, Seweryn M, Rempala GA, Pabla SS, McIndoe RA, Denning TL, Bry L, Kraj P, Kisielow P, Ignatowicz L (2013) Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature 497:258–262
CrossRef
Google scholar
|
[14] |
Chinen T, Kannan AK, Levine AG, Fan X, Klein U, Zheng Y, Gasteiger G, Feng Y, Fontenot JD, Rudensky AY (2016) An essential role for the IL-2 receptor in Treg cell function. Nat Immunol 17:1322–1333
CrossRef
Google scholar
|
[15] |
Colpitts SL, Stonier SW, Stoklasek TA, Root SH, Aguila HL, Schluns KS, Lefrancois L (2013) Transcriptional regulation of IL-15 expression during hematopoiesis. J Immunol 191:3017–3024
CrossRef
Google scholar
|
[16] |
Coquet JM, Ribot JC, Babala N, Middendorp S, van der Horst G, Xiao Y, Neves JF, Fonseca-Pereira D, Jacobs H, Pennington DJ
CrossRef
Google scholar
|
[17] |
Cowan JE, McCarthy NI, Anderson G (2016) CCR7 controls thymus recirculation, but not production and emigration, of Foxp3(+) T Cells. Cell reports 14:1041–1048
CrossRef
Google scholar
|
[18] |
Cui G, Hara T, Simmons S, Wagatsuma K, Abe A, Miyachi H, Kitano S, Ishii M, Tani-ichi S, Ikuta K (2014) Characterization of the IL-15 niche in primary and secondary lymphoid organs in vivo. Proc Natl Acad Sci USA 111:1915–1920
CrossRef
Google scholar
|
[19] |
Cuss SM, Green EA (2012) Abrogation of CD40-CD154 signaling impedes the homeostasis of thymic resident regulatory T cells by altering the levels of IL-2, but does not affect regulatory T cell development. J Immunol 189:1717–1725
CrossRef
Google scholar
|
[20] |
D’Cruz LM, Klein L (2005) Development and function of agonistinduced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 6:1152–1159
CrossRef
Google scholar
|
[21] |
De Smedt M, Verhasselt B, Kerre T, Vanhecke D, Naessens E, Leclercq G, Renauld JC, Van Snick J, Plum J (2000) Signals from the IL-9 receptor are critical for the early stages of human intrathymic T cell development. J Immunol 164:1761–1767
CrossRef
Google scholar
|
[22] |
Fahlen L, Read S, Gorelik L, Hurst SD, Coffman RL, Flavell RA, Powrie F (2005) T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med 201:737–746
CrossRef
Google scholar
|
[23] |
Fisson S, Darrasse-Jeze G, Litvinova E, Septier F, Klatzmann D, Liblau R, Salomon BL (2003) Continuous activation of autoreactive CD4+ CD25+ regulatory T Cells in the steady state. J Exp Med 198:737–746
CrossRef
Google scholar
|
[24] |
Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang H-D, Bopp T, Schmitt E
CrossRef
Google scholar
|
[25] |
Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4(+)CD25(+) regulatory T cells. Nat Immunol 3:3
CrossRef
Google scholar
|
[26] |
Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 6:1142–1151
CrossRef
Google scholar
|
[27] |
Hale JS, Fink PJ (2009) Back to the thymus: peripheral T cells come home. Immunol Cell Biol 87:58–64
CrossRef
Google scholar
|
[28] |
Hanabuchi S, Ito T, Park WR, Watanabe N, Shaw JL, Roman E, Arima K, Wang YH, Voo KS, Cao W
CrossRef
Google scholar
|
[29] |
Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY (2004) Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21:267–277
CrossRef
Google scholar
|
[30] |
Hu Z, Lancaster JN, Sasiponganan C, Ehrlich LI (2015) CCR4 promotes medullary entry and thymocyte-dendritic cell interactions required for central tolerance. J Exp Med 212:1947–1965
CrossRef
Google scholar
|
[31] |
Josefowicz SZ, Lu LF, Rudensky AY (2012a) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564
CrossRef
Google scholar
|
[32] |
Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T, Zheng Y, Umetsu DT, Rudensky AY (2012b) Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482:395–399
CrossRef
Google scholar
|
[33] |
Khailaie S, Robert PA, Toker A, Huehn J, Meyer-Hermann M (2014) A signal integration model of thymic selection and natural regulatory T cell commitment. J Immunol 193:5983–5996
CrossRef
Google scholar
|
[34] |
Kieback E, Hilgenberg E, Stervbo U, Lampropoulou V, Shen P, Bunse M, Jaimes Y, Boudinot P, Radbruch A, Klemm U
CrossRef
Google scholar
|
[35] |
Kim HJ, Cantor H (2011) Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells. Sem Immunol 23:446–452
CrossRef
Google scholar
|
[36] |
Kim HP, Leonard WJ (2007) CREB/ATF-dependent T cell receptorinduced FoxP3 gene expression: a role for DNA methylation. J Exp Med 204:1543–1551
CrossRef
Google scholar
|
[37] |
Kisielow P, Miazek A (1995) Positive selection of Tcells: rescue from programmed cell death and differentiation require continual engagement of the T cell receptor. J Exp Med 181:1975–1984
CrossRef
Google scholar
|
[38] |
Kitagawa Y, Ohkura N, Kidani Y, Vandenbon A, Hirota K, Kawakami R, Yasuda K, Motooka D, Nakamura S, Kondo M
CrossRef
Google scholar
|
[39] |
Klein L, Jovanovic K (2011) Regulatory T cell lineage commitment in the thymus. Sem Immunol 23:401–409
CrossRef
Google scholar
|
[40] |
Klein L, Hinterberger M, Wirnsberger G, Kyewski B (2009) Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol 9:833–844
CrossRef
Google scholar
|
[41] |
Konkel JE, Jin W, Abbatiello B, Grainger JR, Chen W (2014) Thymocyte apoptosis drives the intrathymic generation of regulatory T cells. Proc Natl Acad Sci USA 111:E465–E473
CrossRef
Google scholar
|
[42] |
Kurd N, Robey EA (2016) T-cell selection in the thymus: a spatial and temporal perspective. Immunol Rev 271:114–126
CrossRef
Google scholar
|
[43] |
Kyewski B, Klein L (2006) A central role for central tolerance. Annu Rev Immunol 24:571–606
CrossRef
Google scholar
|
[44] |
Laufer TM, DeKoning J, Markowitz JS, Lo D, Glimcher LH (1996) Unopposed positive selection and autoreactivity in mice expressing class II MHC only on thymic cortex. Nature 383:81–85
CrossRef
Google scholar
|
[45] |
Le Borgne M, Ladi E, Dzhagalov I, Herzmark P, Liao YF, Chakraborty AK, Robey EA (2009) The impact of negative selection on thymocyte migration in the medulla. Nat Immunol 10:823–830
CrossRef
Google scholar
|
[46] |
Li MO, Sanjabi S, Flavell RA (2006) Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and-independent mechanisms. Immunity 25:455–471
CrossRef
Google scholar
|
[47] |
Lio CW, Hsieh CS (2008) A two-step process for thymic regulatory T cell development. Immunity 28:100–111
CrossRef
Google scholar
|
[48] |
Liston A, Nutsch KM, Farr AG, Lund JM, Rasmussen JP, Koni PA, Rudensky AY (2008) Differentiation of regulatory Foxp3+ T cells in the thymic cortex. Proc Natl Acad Sci USA 105:11903–11908
CrossRef
Google scholar
|
[49] |
Liu Y, Zhang P, Li J, Kulkarni AB, Perruche S, Chen W (2008) A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol 9:632–640
CrossRef
Google scholar
|
[50] |
Love PE, Bhandoola A (2011) Signal integration and crosstalk during thymocyte migration and emigration. Nat Rev Immunol 11:469–477
CrossRef
Google scholar
|
[51] |
Lucas B, McCarthy NI, Baik S, Cosway E, James KD, Parnell SM, White AJ, Jenkinson WE, Anderson G (2016) Control of the thymic medulla and its influence on alphabetaT-cell development. Immunol Rev 271:23–37
CrossRef
Google scholar
|
[52] |
Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y, Owen DL, Schenkel JM, Boomer JS, Green JM, Yagita H
CrossRef
Google scholar
|
[53] |
Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, Amit AS, Kang C, Geddes JE, Allison JP (2013) Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339:1219–1224
CrossRef
Google scholar
|
[54] |
Malek TR, Porter BO, Codias EK, Scibelli P, 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
CrossRef
Google scholar
|
[55] |
Malek TR, Yu A, Vincek V, Scibelli P, 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
CrossRef
Google scholar
|
[56] |
Marie JC, Letterio JJ, Gavin M, Rudensky AY (2005) TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+ CD25+ regulatory T cells. J Exp Med 201:1061–1067
CrossRef
Google scholar
|
[57] |
Marie JC, Liggitt D, Rudensky AY (2006) Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25:441–454
CrossRef
Google scholar
|
[58] |
Marshall D, Sinclair C, Tung S, Seddon B (2014) Differential requirement for IL-2 and IL-15 during bifurcated development of thymic regulatory T cells. J Immunol 193:5525–5533
CrossRef
Google scholar
|
[59] |
Mazzucchelli R, Hixon JA, Spolski R, Chen X, Li WQ, Hall VL, Willette-Brown J, Hurwitz AA, Leonard WJ, Durum SK (2008) Development of regulatory Tcells requires IL-7Ralpha stimulation by IL-7 or TSLP. Blood 112:3283–3292
CrossRef
Google scholar
|
[60] |
McCaughtry TM, Wilken MS, Hogquist KA (2007) Thymic emigration revisited. J Exp Med 204:2513–2520
CrossRef
Google scholar
|
[61] |
McCaughtry TM, Baldwin TA, Wilken MS, Hogquist KA (2008) Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla. J Exp Med 205:2575–2584
CrossRef
Google scholar
|
[62] |
Meredith M, Zemmour D, Mathis D, Benoist C (2015) Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat Immunol 16:942–949
CrossRef
Google scholar
|
[63] |
Ohigashi I, Kozai M, Takahama Y (2016) Development and developmental potential of cortical thymic epithelial cells. Immunol Rev 271:10–22
CrossRef
Google scholar
|
[64] |
Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, Osaki M, Tanaka Y, Yamashita R, Nakano N
CrossRef
Google scholar
|
[65] |
Ouyang W, Beckett O, Ma Q, Li MO (2010) Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32:642–653
CrossRef
Google scholar
|
[66] |
Pelly VS, Kannan Y, Coomes SM, Entwistle LJ, Ruckerl D, Seddon B, MacDonald AS, McKenzie A, Wilson MS (2016) IL-4-producing ILC2s are required for the differentiation of TH2 cells following Heligmosomoides polygyrus infection. Mucosal Immunol 9:1407–1417
CrossRef
Google scholar
|
[67] |
Pennington DJ, Silva-Santos B, Silberzahn T, Escorcio-Correia M, Woodward MJ, Roberts SJ, Smith AL, Dyson PJ, Hayday AC (2006) Early events in the thymus affect the balance of effector and regulatory T cells. Nature 444:1073–1077
CrossRef
Google scholar
|
[68] |
Popmihajlov Z, Xu D, Morgan H, Milligan Z, Smith KA (2012) Conditional IL-2 gene deletion: consequences for T cell proliferation. Front Immunol 3:102
CrossRef
Google scholar
|
[69] |
Ribot J, Enault G, Pilipenko S, Huchenq A, Calise M, Hudrisier D, Romagnoli P, van Meerwijk JPM (2007) Shaping of the autoreactive regulatory T cell repertoire by thymic cortical positive selection. J Immunol 179:6741–6748
CrossRef
Google scholar
|
[70] |
Romagnoli P, Hudrisier D, van Meerwijk JPM (2002) Preferential recognition of self-antigens despite normal thymic deletion of CD4+CD25+ regulatory T cells. J Immunol 168:1644–1648
CrossRef
Google scholar
|
[71] |
Romagnoli P, Ribot J, Tellier J, van Meerwijk JPM (2008) Thymic and peripheral generation of CD4+Foxp3+ regulatory Tcells. In: Jiang S (ed) Regulatory T cells and clinical application. Springer Science+Business Media, New York, pp 29–55
CrossRef
Google scholar
|
[72] |
Sadlack B, Lohler J, Schorle H, Klebb G, Haber H, Sickel E, Noelle RJ, Horak I (1995) Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur J Immunol 25:3053–3059
CrossRef
Google scholar
|
[73] |
Sakaguchi S, Miyara M, Costantino CM, Hafler DA (2010) FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10:490–500
CrossRef
Google scholar
|
[74] |
Shevach EM (2011) Biological functions of regulatory T cells. Adv Immunol 112:137–176
CrossRef
Google scholar
|
[75] |
Shitara S, Hara T, Liang B, Wagatsuma K, Zuklys S, Hollander GA, Nakase H, Chiba T, Tani-ichi S, Ikuta K (2013) IL-7 produced by thymic epithelial cells plays a major role in the development of thymocytes and TCRgammadelta+ intraepithelial lymphocytes. J Immunol 190:6173–6179
CrossRef
Google scholar
|
[76] |
Soper DM, Kasprowicz DJ, Ziegler SF (2007) IL-2Rbeta links IL-2R signaling with Foxp3 expression. Eur J Immunol 37:1817–1826
CrossRef
Google scholar
|
[77] |
Stritesky GL, Xing Y, Erickson JR, Kalekar LA, Wang X, Mueller DL, Jameson SC, Hogquist KA (2013) Murine thymic selection quantified using a unique method to capture deleted T cells. Proc Natl Acad Sci USA 110:4679–4684
CrossRef
Google scholar
|
[78] |
Sun J, Furio L, Mecheri R, van der Does AM, Lundeberg E, Saveanu L, Chen Y, van Endert P, Agerberth B, Diana J (2015) Pancreatic beta-cells limit autoimmune diabetes via an immunoregulatory antimicrobial peptide expressed under the influence of the gut microbiota. Immunity 43:304–317
CrossRef
Google scholar
|
[79] |
Suzuki H, Kundig T, Furlonger C, Wakeham A, Timms E, Matsuyama T, Schmits R, Simard J, Ohashi P, Griesser H
CrossRef
Google scholar
|
[80] |
Suzuki H, Zhou YW, Kato M, Mak TW, Nakashima I (1999) Normal regulatory alpha/beta T cells effectively eliminate abnormally activated T cells lacking the interleukin 2 receptor beta in vivo. J Exp Med 190:1561–1572
CrossRef
Google scholar
|
[81] |
Tai X, Cowan M, Feigenbaum L, Singer A (2005) CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol 6:152–162
CrossRef
Google scholar
|
[82] |
Tai X, Erman B, Alag A, Mu J, Kimura M, Katz G, Guinter T, McCaughtry T, Etzensperger R, Feigenbaum L
CrossRef
Google scholar
|
[83] |
Takaba H, Morishita Y, Tomofuji Y, Danks L, Nitta T, Komatsu N, Kodama T, Takayanagi H (2015) Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163:975–987
CrossRef
Google scholar
|
[84] |
Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK, Zheng XX, Strom TB, Bluestone JA (2003) Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol 171:3348–3352
CrossRef
Google scholar
|
[85] |
Tani-ichi S, Shimba A, Wagatsuma K, Miyachi H, Kitano S, Imai K, Hara T, Ikuta K (2013) Interleukin-7 receptor controls development and maturation of late stages of thymocyte subpopulations. Proc Natl Acad Sci USA 110:612–617
CrossRef
Google scholar
|
[86] |
Thiault N, Darrigues J, Adoue V, Gros M, Binet B, Perals C, Leobon B, Fazilleau N, Joffre OP, Robey EA
CrossRef
Google scholar
|
[87] |
Toker A, Engelbert D, Garg G, Polansky JK, Floess S, Miyao T, Baron U, Duber S, Geffers R, Giehr P
CrossRef
Google scholar
|
[88] |
Ueno T, Saito F, Gray DH, Kuse S, Hieshima K, Nakano H, Kakiuchi T, Lipp M, Boyd RL, Takahama Y (2004) CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J Exp Med 200:493–505
CrossRef
Google scholar
|
[89] |
Valitutti S, Muller S, Cella M, Padovan E, Lanzavecchia A (1995) Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature 375:148–151
CrossRef
Google scholar
|
[90] |
Vang KB, Yang J, Mahmud SA, Burchill MA, Vegoe AL, Farrar MA (2008) IL-2, -7, and-15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development. J Immunol 181:3285–3290
CrossRef
Google scholar
|
[91] |
von Freeden-Jeffry U, Vieira P, Lucian LA, McNeil T, Burdach SE, Murray R (1995) Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med 181:1519–1526
CrossRef
Google scholar
|
[92] |
Vuddamalay, Y., and van Meerwijk, J. (2017). CD28neg and CD28low CD8+ regulatory T cells: Of Mice and Men. Front Immunol 8.
CrossRef
Google scholar
|
[93] |
Watanabe N, Wang YH, Lee HK, Ito T, Wang YH, Cao W, Liu YJ (2005) Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory Tcells in human thymus. Nature 436:1181–1185
CrossRef
Google scholar
|
[94] |
Weist BM, Kurd N, Boussier J, Chan SW, Robey EA (2015) Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition. Nat Immunol 16:635–641
CrossRef
Google scholar
|
[95] |
Wilkinson RW, Anderson G, Owen JJ, Jenkinson EJ (1995) Positive selection of thymocytes involves sustained interactions with the thymic microenvironment. J Immunol 155:5234–5240
|
[96] |
Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW (1995) Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3(4):521–530
CrossRef
Google scholar
|
[97] |
Wirnsberger G, Mair F, Klein L (2009) Regulatory T cells differentiation of thymocytes does not require a dedicated antigenpresenting cell but is under T cell-intrinsic developmental control. Proc Natl Acad Sci USA 106:10278–10283
CrossRef
Google scholar
|
[98] |
Wolf M, Schimpl A, 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
CrossRef
Google scholar
|
[99] |
Xu Z, Ho S, Chang CC, Zhang QY, Vasilescu ER, Vlad G, Suciu-Foca N (2016) Molecular and cellular characterization of human CD8 T suppressor cells. Front Immunol 7:549
CrossRef
Google scholar
|
[100] |
Yamano T, Nedjic J, Hinterberger M, Steinert M, Koser S, Pinto S, Gerdes N, Lutgens E, Ishimaru N, Busslinger M
CrossRef
Google scholar
|
[101] |
Yang S, Fujikado N, Kolodin D, Benoist C, Mathis D (2015) Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348:589–594
CrossRef
Google scholar
|
[102] |
Yao Z, Kanno Y, Kerenyi M, Stephens G, Durant L, Watford WT, Laurence A, Robinson GW, Shevach EM, Moriggl R
CrossRef
Google scholar
|
[103] |
Yu W, Nagaoka H, Jankovic M, Misulovin Z, Suh H, Rolink A, Melchers F, Meffre E, Nussenzweig MC (1999) Continued RAG expression in late stages of B cell development and no apparent re-induction after immunization. Nature 400:682–687
CrossRef
Google scholar
|
[104] |
Yue X, Trifari S, Aijo T, Tsagaratou A, Pastor WA, Zepeda-Martinez JA, Lio CW, Li X, Huang Y, Vijayanand P
CrossRef
Google scholar
|
[105] |
Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY (2010) Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463:808–812
CrossRef
Google scholar
|
/
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