1932

Abstract

A high diversity of αβ T cell receptors (TCRs), capable of recognizing virtually any pathogen but also self-antigens, is generated during T cell development in the thymus. Nevertheless, a strict developmental program supports the selection of a self-tolerant T cell repertoire capable of responding to foreign antigens. The steps of T cell selection are controlled by cortical and medullary stromal niches, mainly composed of thymic epithelial cells and dendritic cells. The integration of important cues provided by these specialized niches, including () the TCR signal strength induced by the recognition of self-peptide-MHC complexes, () costimulatory signals, and () cytokine signals, critically controls T cell repertoire selection. This review discusses our current understanding of the signals that coordinate positive selection, negative selection, and agonist selection of Foxp3+ regulatory T cells. It also highlights recent advances that have unraveled the functional diversity of thymic antigen-presenting cell subsets implicated in T cell selection.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-101320-022432
2022-04-26
2024-12-10
Loading full text...

Full text loading...

/deliver/fulltext/immunol/40/1/annurev-immunol-101320-022432.html?itemId=/content/journals/10.1146/annurev-immunol-101320-022432&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Zarnitsyna VI, Evavold BD, Schoettle LN, Blattman JN, Antia R. 2013. Estimating the diversity, completeness, and cross-reactivity of the T cell repertoire. Front. Immunol. 4:485
    [Google Scholar]
  2. 2. 
    Nikolich-Žugich J, Slifka MK, Messaoudi I. 2004. The many important facets of T-cell repertoire diversity. Nat. Rev. Immunol. 4:2123–32
    [Google Scholar]
  3. 3. 
    Petrie HT, Zúñiga-Pflücker JC. 2007. Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu. Rev. Immunol. 25:649–79
    [Google Scholar]
  4. 4. 
    Lind EF, Prockop SE, Porritt HE, Petrie HT. 2001. Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J. Exp. Med. 194:2127–34
    [Google Scholar]
  5. 5. 
    Porritt HE, Gordon K, Petrie HT 2003. Kinetics of steady-state differentiation and mapping of intrathymic-signaling environments by stem cell transplantation in nonirradiated mice. J. Exp. Med. 198:6957–62
    [Google Scholar]
  6. 6. 
    Godfrey DI, Kennedy J, Suda T, Zlotnik A. 1993. A developmental pathway involving four phenotypically and functionally distinct subsets of CD3CD4CD8 triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J. Immunol. 150:104244–52
    [Google Scholar]
  7. 7. 
    Cumano A, Berthault C, Ramond C, Petit M, Golub R et al. 2019. New molecular insights into immune cell development. Annu. Rev. Immunol. 37:497–519
    [Google Scholar]
  8. 8. 
    Buono M, Facchini R, Matsuoka S, Thongjuea S, Waithe D et al. 2016. A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors. Nat. Cell Biol. 18:2157–67
    [Google Scholar]
  9. 9. 
    Yui MA, Feng N, Rothenberg EV 2010. Fine-scale staging of T cell lineage commitment in adult mouse thymus. J. Immunol. 185:1284–93
    [Google Scholar]
  10. 10. 
    Hozumi K, Mailhos C, Negishi N, Hirano KI, Yahata T et al. 2008. Delta-like 4 is indispensable in thymic environment specific for T cell development. J. Exp. Med. 205:112507–13
    [Google Scholar]
  11. 11. 
    Koch U, Fiorini E, Benedito R, Besseyrias V, Schuster-Gossler K et al. 2008. Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J. Exp. Med. 205:112515–23
    [Google Scholar]
  12. 12. 
    Hosokawa H, Rothenberg EV. 2021. How transcription factors drive choice of the T cell fate. Nat. Rev. Immunol. 21:162–76
    [Google Scholar]
  13. 13. 
    Kreslavsky T, Gleimer M, Miyazaki M, Choi Y, Gagnon E et al. 2012. β-Selection-induced proliferation is required for αβ T cell differentiation. Immunity 37:5840–53
    [Google Scholar]
  14. 14. 
    Mallis RJ, Bai K, Arthanari H, Hussey RE, Handley M et al. 2015. Pre-TCR ligand binding impacts thymocyte development before αβTCR expression. PNAS 112:278373–78
    [Google Scholar]
  15. 15. 
    MacDonald HR, Budd RC, Howe RC. 1988. A CD3 subset of CD48+ thymocytes: a rapidly cycling intermediate in the generation of CD4+8+ cells. Eur. J. Immunol. 18:4519–24
    [Google Scholar]
  16. 16. 
    Singer A, Adoro S, Park JH 2008. Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice. Nat. Rev. Immunol. 8:788–801
    [Google Scholar]
  17. 17. 
    Surh CD, Sprent J. 1994. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 372:6501100–3
    [Google Scholar]
  18. 18. 
    McDonald BD, Bunker JJ, Erickson SA, Oh-Hora M, Bendelac A. 2015. Crossreactive αβ T cell receptors are the predominant targets of thymocyte negative selection. Immunity 43:5859–69
    [Google Scholar]
  19. 19. 
    Kurd N, Robey EA. 2016. T-cell selection in the thymus: a spatial and temporal perspective. Immunol. Rev. 271:1114–26
    [Google Scholar]
  20. 20. 
    Davey GM, Schober SL, Endrizzi BT, Dutcher AK, Jameson SC, Hogquist KA 1998. Preselection thymocytes are more sensitive to T cell receptor stimulation than mature T cells. J. Exp. Med. 188:101867–74
    [Google Scholar]
  21. 21. 
    Ebert PJR, Ehrlich LIR, Davis MM. 2008. Low ligand requirement for deletion and lack of synapses in positive selection enforce the gauntlet of thymic T cell maturation. Immunity 29:5734–45
    [Google Scholar]
  22. 22. 
    Linette GP, Grusby MJ, Hedrick SM, Hansen TH, Glimcher LH, Korsmeyer SJ. 1994. Bcl-2 is upregulated at the CD4+ CD8+ stage during positive selection and promotes thymocyte differentiation at several control points. Immunity 1:3197–205
    [Google Scholar]
  23. 23. 
    Lyu J, Wang L, Lu L 2019. Thymocyte selection: from signaling to epigenetic regulation. Adv. Immunol. 144:1–22
    [Google Scholar]
  24. 24. 
    Canté-Barrett K, Winslow MM, Crabtree GR 2007. Selective role of NFATc3 in positive selection of thymocytes. J. Immunol. 179:1103–10
    [Google Scholar]
  25. 25. 
    Ross JO, Melichar HJ, Au-Yeung BB, Herzmark P, Weiss A, Robey EA. 2014. Distinct phases in the positive selection of CD8+ T cells distinguished by intrathymic migration and T-cell receptor signaling patterns. PNAS 111:25E2550–58
    [Google Scholar]
  26. 26. 
    Neilson JR, Winslow MM, Hur EM, Crabtree GR. 2004. Calcineurin B1 is essential for positive but not negative selection during thymocyte development. Immunity 20:3255–66
    [Google Scholar]
  27. 27. 
    Melichar HJ, Ross JO, Herzmark P, Hogquist KA, Robey EA. 2013. Distinct temporal patterns of T cell receptor signaling during positive versus negative selection in situ. Sci. Signal. 6:297ra92
    [Google Scholar]
  28. 28. 
    Lutes LK, Steier Z, McIntyre LL, Pandey S, Kaminski J et al. 2021. T cell self-reactivity during thymic development dictates the timing of positive selection. eLife 10:e65435
    [Google Scholar]
  29. 29. 
    Ito-Kureha T, Miyao T, Nishijima S, Suzuki T, Koizumi S-I et al. 2020. The CCR4-NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression. Nat. Commun. 11:16169
    [Google Scholar]
  30. 30. 
    Fischer AM, Katayama CD, Pagès G, Pouysségur J, Hedrick SM 2005. The role of Erk1 and Erk2 in multiple stages of T cell development. Immunity 23:4431–43
    [Google Scholar]
  31. 31. 
    Zheng M, Li D, Zhao Z, Shytikov D, Xu Q et al. 2019. Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection. PNAS 116:2512422–27
    [Google Scholar]
  32. 32. 
    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. 205:112575–84
    [Google Scholar]
  33. 33. 
    Daley SR, Hu DY, Goodnow CC. 2013. Helios marks strongly autoreactive CD4+ T cells in two major waves of thymic deletion distinguished by induction of PD-1 or NF-κB. J. Exp. Med. 210:2269–85
    [Google Scholar]
  34. 34. 
    Daley SR, Teh C, Hu DY, Strasser A, Gray DHD. 2017. Cell death and thymic tolerance. Immunol. Rev. 277:9–20
    [Google Scholar]
  35. 35. 
    Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L et al. 2002. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415:6874922–26
    [Google Scholar]
  36. 36. 
    Stritesky GL, Xing Y, Erickson JR, Kalekar LA, Wang X et al. 2013. Murine thymic selection quantified using a unique method to capture deleted T cells. PNAS 110:124679–84
    [Google Scholar]
  37. 37. 
    Gray DHD, Kupresanin F, Berzins SP, Herold MJ, O'Reilly LA et al. 2012. The BH3-only proteins Bim and Puma cooperate to impose deletional tolerance of organ-specific antigens. Immunity 37:3451–62
    [Google Scholar]
  38. 38. 
    Kwan J, Killeen N. 2004. CCR7 directs the migration of thymocytes into the thymic medulla. J. Immunol. 172:73999–4007
    [Google Scholar]
  39. 39. 
    Ueno T, Saito F, Gray DHD, Kuse S, Hieshima K et al. 2004. CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J. Exp. Med. 200:4493–505
    [Google Scholar]
  40. 40. 
    Lopes N, Sergé A, Ferrier P, Irla M. 2015. Thymic crosstalk coordinates medulla organization and T-cell tolerance induction. Front. Immunol. 6:365
    [Google Scholar]
  41. 41. 
    Hogquist KA, Xing Y, Hsu F-C, Shapiro VS. 2015. T cell adolescence: maturation events beyond positive selection. J. Immunol. 195:41351–57
    [Google Scholar]
  42. 42. 
    Kisielow P, Blüthmann H, Staerz UD, Steinmetz M, Von Boehmer H. 1988. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333:6175742–46
    [Google Scholar]
  43. 43. 
    Baldwin TA, Sandau MM, Jameson SC, Hogquist KA 2005. The timing of TCRα expression critically influences T cell development and selection. J. Exp. Med. 202:1111–21
    [Google Scholar]
  44. 44. 
    Moon JJ, Dash P, Oguin TH, McClaren JL, Chu HH et al. 2011. Quantitative impact of thymic selection on Foxp3+ and Foxp3 subsets of self-peptide/MHC class II-specific CD4+ T cells. PNAS 108:3514602–7
    [Google Scholar]
  45. 45. 
    Malhotra D, Linehan JL, Dileepan T, Lee YJ, Purtha WE et al. 2016. Tolerance is established in polyclonal CD4+ T cells by distinct mechanisms, according to self-peptide expression patterns. Nat. Immunol. 17:2187–95
    [Google Scholar]
  46. 46. 
    Sinclair C, Bains I, Yates AJ, Seddon B. 2013. Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system. PNAS 110:31E2905–14
    [Google Scholar]
  47. 47. 
    Gonzalez-Duque S, Azoury ME, Colli ML, Afonso G, Turatsinze JV et al. 2018. Conventional and neo-antigenic peptides presented by β cells are targeted by circulating naïve CD8+ T cells in type 1 diabetic and healthy donors. Cell Metab 28:6946–60.e6
    [Google Scholar]
  48. 48. 
    Culina S, Lalanne AI, Afonso G, Cerosaletti K, Pinto S et al. 2018. Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. Sci. Immunol. 3:204013
    [Google Scholar]
  49. 49. 
    Yu W, Jiang N, Ebert PJR, Kidd BA, Müller S et al. 2015. Clonal deletion prunes but does not eliminate self-specific αβ CD8+ T lymphocytes. Immunity 42:5929–41
    [Google Scholar]
  50. 50. 
    Bouneaud C, Kourilsky P, Bousso P. 2000. Impact of negative selection on the T cell repertoire reactive to a self-peptide: A large fraction of T cell clones escapes clonal deletion. Immunity 13:6829–40
    [Google Scholar]
  51. 51. 
    Kuchroo VK, Anderson AC, Waldner H, Munder M, Bettelli E, Nicholson LB 2002. T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire. Annu. Rev. Immunol. 20:101–23
    [Google Scholar]
  52. 52. 
    Klein L, Klugmann M, Nave KA, Tuohy VK, Kyewski B. 2000. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat. Med. 6:156–61
    [Google Scholar]
  53. 53. 
    Legoux FP, Lim JB, Cauley AW, Dikiy S, Ertelt J et al. 2015. CD4+ T cell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion. Immunity 43:5896–908
    [Google Scholar]
  54. 54. 
    Hsieh CS, Lee HM, Lio CWJ. 2012. Selection of regulatory T cells in the thymus. Nat. Rev. Immunol. 12:157–67
    [Google Scholar]
  55. 55. 
    Klein L, Robey EA, Hsieh CS. 2019. Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation. Nat. Rev. Immunol. 19:7–18
    [Google Scholar]
  56. 56. 
    Hogquist KA, Jameson SC. 2014. The self-obsession of T cells: how TCR signaling thresholds affect fate “decisions” and effector function. Nat. Immunol. 15:9815–23
    [Google Scholar]
  57. 57. 
    Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE et al. 2001. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2:4301–6
    [Google Scholar]
  58. 58. 
    Larkin J, Rankin AL, Picca CC, Riley MP, Jenks SA et al. 2008. CD4+ CD25+ regulatory T cell repertoire formation shaped by differential presentation of peptides from a self-antigen. J. Immunol. 180:42149–57
    [Google Scholar]
  59. 59. 
    Walker LSK, Chodos A, Eggena M, Dooms H, Abbas AK. 2003. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J. Exp. Med. 198:2249–58
    [Google Scholar]
  60. 60. 
    Aschenbrenner K, D'Cruz LM, Vollmann EH, Hinterberger M, Emmerich J et al. 2007. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol. 8:4351–58
    [Google Scholar]
  61. 61. 
    Kawahata K, Misaki Y, Yamauchi M, Tsunekawa S, Setoguchi K et al. 2002. 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. 168:94399–405
    [Google Scholar]
  62. 62. 
    Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. 2006. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat. Immunol. 7:4401–10
    [Google Scholar]
  63. 63. 
    Klawon DEJ, Gilmore DC, Leonard JD, Miller CH, Chao JL et al. 2021. Altered selection on a single self-ligand promotes susceptibility to organ-specific T cell infiltration. J. Exp. Med. 218:6e20200701
    [Google Scholar]
  64. 64. 
    Leung MWL, Shen S, Lafaille JJ. 2009. TCR-dependent differentiation of thymic Foxp3+ cells is limited to small clonal sizes. J. Exp. Med. 206:102121–30
    [Google Scholar]
  65. 65. 
    Bautista JL, Lio CWJ, Lathrop SK, Forbush K, Liang Y et al. 2009. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat. Immunol. 10:6610–17
    [Google Scholar]
  66. 66. 
    Irla M, Guerri L, Guenot J, Sergé A, Lantz O et al. 2012. Antigen recognition by autoreactive CD4+ thymocytes drives homeostasis of the thymic medulla. PLOS ONE 7:12e52591
    [Google Scholar]
  67. 67. 
    Irla M, Hugues S, Gill J, Nitta T, Hikosaka Y et al. 2008. Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29:3451–63
    [Google Scholar]
  68. 68. 
    Hemmers S, Schizas M, Azizi E, Dikiy S, Zhong Y et al. 2019. IL-2 production by self-reactive CD4 thymocytes scales regulatory T cell generation in the thymus. J. Exp. Med. 216:112466–78
    [Google Scholar]
  69. 69. 
    Lio CWJ, Hsieh CS. 2008. A two-step process for thymic regulatory T cell development. Immunity 28:1100–11
    [Google Scholar]
  70. 70. 
    Burchill MA, Yang J, Vang KB, Moon JJ, Chu HH et al. 2008. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 28:1112–21
    [Google Scholar]
  71. 71. 
    Tai X, Erman B, Alag A, Mu J, Kimura M et al. 2013. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 38:61116–28
    [Google Scholar]
  72. 72. 
    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. 193:115525–33
    [Google Scholar]
  73. 73. 
    Owen DL, Mahmud SA, Sjaastad LE, Williams JB, Spanier JA et al. 2019. Thymic regulatory T cells arise via two distinct developmental programs. Nat. Immunol. 20:2195–205
    [Google Scholar]
  74. 74. 
    Wyss L, Stadinski BD, King CG, Schallenberg S, McCarthy NI et al. 2016. Affinity for self antigen selects Treg cells with distinct functional properties. Nat. Immunol. 17:91093–101
    [Google Scholar]
  75. 75. 
    Santamaria JC, Borelli A, Irla M. 2021. Regulatory T cell heterogeneity in the thymus: impact on their functional activities. Front. Immunol. 12:643153
    [Google Scholar]
  76. 76. 
    Raffin C, Vo LT, Bluestone JA. 2020. Treg cell-based therapies: challenges and perspectives. Nat. Rev. Immunol. 20:158–72
    [Google Scholar]
  77. 77. 
    Ferreira LMR, Muller YD, Bluestone JA, Tang Q. 2019. Next-generation regulatory T cell therapy. Nat. Rev. Drug Discov. 18:10749–69
    [Google Scholar]
  78. 78. 
    Dijke IE, Hoeppli RE, Ellis T, Pearcey J, Huang Q et al. 2016. Discarded human thymus is a novel source of stable and long-lived therapeutic regulatory T cells. Am. J. Transplant. 16:158–71
    [Google Scholar]
  79. 79. 
    Bautista JL, Cramer NT, Miller CN, Chavez J, Berrios DI et al. 2021. Single-cell transcriptional profiling of human thymic stroma uncovers novel cellular heterogeneity in the thymic medulla. Nat. Commun. 12:11096
    [Google Scholar]
  80. 80. 
    Holländer GA, Wang B, Nichogiannopoulou A, Platenburg PP, Van Ewijk W et al. 1995. Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373:6512350–53
    [Google Scholar]
  81. 81. 
    Shakib S, Desanti GE, Jenkinson WE, Parnell SM, Jenkinson EJ, Anderson G. 2009. Checkpoints in the development of thymic cortical epithelial cells. J. Immunol. 182:1130–37
    [Google Scholar]
  82. 82. 
    Gossens K, Naus S, Corbel SY, Lin S, Rossi FMV et al. 2009. Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25. J. Exp. Med. 206:4761–78
    [Google Scholar]
  83. 83. 
    Plotkin J, Prockop SE, Lepique A, Petrie HT 2003. Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J. Immunol. 171:94521–27
    [Google Scholar]
  84. 84. 
    Alves NL, Richard-Le Goff O, Huntington ND, Sousa AP, Ribeiro VSG et al. 2009. Characterization of the thymic IL-7 niche in vivo. PNAS 106:51512–17
    [Google Scholar]
  85. 85. 
    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 383:659581–85
    [Google Scholar]
  86. 86. 
    Xing Y, Jameson SC, Hogquist KA 2013. Thymoproteasome subunit-β5T generates peptide-MHC complexes specialized for positive selection. PNAS 110:176979–84
    [Google Scholar]
  87. 87. 
    Sasaki K, Takada K, Ohte Y, Kondo H, Sorimachi H et al. 2015. Thymoproteasomes produce unique peptide motifs for positive selection of CD8+ T cells. Nat. Commun. 6:7484
    [Google Scholar]
  88. 88. 
    Honey K, Nakagawa T, Peters C, Rudensky A. 2002. Cathepsin L regulates CD4+ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands. J. Exp. Med. 195:101349–58
    [Google Scholar]
  89. 89. 
    Gommeaux J, Grégoire C, Nguessan P, Richelme M, Malissen M et al. 2009. Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur. J. Immunol. 39:4956–64
    [Google Scholar]
  90. 90. 
    Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L 2008. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455:7211396–400
    [Google Scholar]
  91. 91. 
    Wekerle H, Ketelsen UP, Ernst M. 1980. Thymic nurse cells: lymphoepithelial cell complexes in murine thymuses; morphological and serological characterization. J. Exp. Med. 151:4925–44
    [Google Scholar]
  92. 92. 
    Nakagawa Y, Ohigashi I, Nitta T, Sakata M, Tanaka K et al. 2012. Thymic nurse cells provide microenvironment for secondary T cell receptor α rearrangement in cortical thymocytes. PNAS 109:5020572–77
    [Google Scholar]
  93. 93. 
    Gray DHD, Seach N, Ueno T, Milton MK, Liston A et al. 2006. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108:123777–85
    [Google Scholar]
  94. 94. 
    Gäbler J, Arnold J, Kyewski B 2007. Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. Eur. J. Immunol. 37:123363–72
    [Google Scholar]
  95. 95. 
    Smith KM, Olson DC, Hirose R, Hanahan D. 1997. Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance. Int. Immunol. 9:9)1355–65
    [Google Scholar]
  96. 96. 
    Jolicoeur C, Hanahan D, Smith KM 1994. T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in thymus. PNAS 91:14670711
    [Google Scholar]
  97. 97. 
    Egwuagu CE, Charukamnoetkanok P, Gery I. 1997. Thymic expression of autoantigens correlates with resistance to autoimmune disease. J. Immunol 159:7310912
    [Google Scholar]
  98. 98. 
    Derbinski J, Schulte A, Kyewski B, Klein L. 2001. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2:111032–39
    [Google Scholar]
  99. 99. 
    Sansom SN, Shikama-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay IC et al. 2014. Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res 24:121918–31
    [Google Scholar]
  100. 100. 
    Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP et al. 2002. Projection of an immunological self shadow within the thymus by the aire protein. Science 298:55971395–401
    [Google Scholar]
  101. 101. 
    Takaba H, Morishita Y, Tomofuji Y, Danks L, Nitta T et al. 2015. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163:4975–87
    [Google Scholar]
  102. 102. 
    Tomofuji Y, Takaba H, Suzuki HI, Benlaribi R, Martinez CDP et al. 2020. Chd4 choreographs self-antigen expression for central immune tolerance. Nat. Immunol. 21:8892–901
    [Google Scholar]
  103. 103. 
    Klein L, Kyewski B, Allen PM, Hogquist KA 2014. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat. Rev. Immunol. 14:377–91
    [Google Scholar]
  104. 104. 
    Gallegos AM, Bevan MJ. 2004. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200:81039–49
    [Google Scholar]
  105. 105. 
    Aichinger M, Wu C, Nedjic J, Klein L 2013. Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance. J. Exp. Med. 210:2287–300
    [Google Scholar]
  106. 106. 
    Hinterberger M, Aichinger M, Da Costa OP, Voehringer D, Hoffmann R, Klein L 2010. Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance. Nat. Immunol. 11:6512–19
    [Google Scholar]
  107. 107. 
    Akiyama N, Shinzawa M, Miyauchi M, Yanai H, Tateishi R et al. 2014. Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation. J. Exp. Med. 211:122425–38
    [Google Scholar]
  108. 108. 
    Hauri-Hohl M, Zuklys S, Holländer GA, Ziegler SF. 2014. A regulatory role for TGF-β signaling in the establishment and function of the thymic medulla. Nat. Immunol. 15:6554–61
    [Google Scholar]
  109. 109. 
    Mouri Y, Nishijima H, Kawano H, Hirota F, Sakaguchi N et al. 2014. NF-κB-inducing kinase in thymic stroma establishes central tolerance by orchestrating cross-talk with not only thymocytes but also dendritic cells. J. Immunol. 193:94356–67
    [Google Scholar]
  110. 110. 
    Lin J, Yang L, Silva HM, Trzeciak A, Choi Y et al. 2016. Increased generation of Foxp3+ regulatory T cells by manipulating antigen presentation in the thymus. Nat. Commun. 7:10562
    [Google Scholar]
  111. 111. 
    Cowan JE, Parnell SM, Nakamura K, Caamano JH, Lane PJL et al. 2013. The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development. J. Exp. Med. 210:4675–81
    [Google Scholar]
  112. 112. 
    Coquet JM, Ribot JC, Ba̧bala N, Middendorp S, van der Horst G et al. 2013. Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway. J. Exp. Med. 210:4715–28
    [Google Scholar]
  113. 113. 
    Kadouri N, Nevo S, Goldfarb Y, Abramson J. 2020. Thymic epithelial cell heterogeneity: TEC by TEC. Nat. Rev. Immunol. 20:239–53
    [Google Scholar]
  114. 114. 
    Irla M. 2021. RANK signaling in the differentiation and regeneration of thymic epithelial cells. Front. Immunol. 11:623265
    [Google Scholar]
  115. 115. 
    Park J-E, Botting RA, Domínguez Conde C, Popescu D-M, Lavaert M et al. 2020. A cell atlas of human thymic development defines T cell repertoire formation. Science 367:6480eaay3224
    [Google Scholar]
  116. 116. 
    van Ewijk W, Shores EW, Singer A. 1994. Crosstalk in the mouse thymus. Immunol. Today 15:5214–17
    [Google Scholar]
  117. 117. 
    Irla M, Hollander G, Reith W. 2010. Control of central self-tolerance induction by autoreactive CD4+ thymocytes. Trends Immunol 31:271–79
    [Google Scholar]
  118. 118. 
    Asano T, Okamoto K, Nakai Y, Tsutsumi M, Muro R et al. 2019. Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone. Nat. Metab. 1:868–75
    [Google Scholar]
  119. 119. 
    Le Borgne M, Ladi E, Dzhagalov I, Herzmark P, Liao YF et al. 2009. The impact of negative selection on thymocyte migration in the medulla. Nat. Immunol. 10:8823–30
    [Google Scholar]
  120. 120. 
    Ohnmacht C, Pullner A, King SBS, Drexler I, Meier S et al. 2009. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J. Exp. Med. 206:3549–59
    [Google Scholar]
  121. 121. 
    Wu L, Shortman K. 2005. Heterogeneity of thymic dendritic cells. Semin. Immunol. 17:4304–12
    [Google Scholar]
  122. 122. 
    Lei Y, Ripen AM, Ishimaru N, Ohigashi I, Nagasawa T et al. 2011. Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J. Exp. Med. 208:2383–94
    [Google Scholar]
  123. 123. 
    Koble C, Kyewski B. 2009. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med. 206:71505–13
    [Google Scholar]
  124. 124. 
    Kroger CJ, Spidale NA, Wang B, Tisch R 2017. Thymic dendritic cell subsets display distinct efficiencies and mechanisms of intercellular MHC transfer. J. Immunol. 198:1249–56
    [Google Scholar]
  125. 125. 
    Gray D, Abramson J, Benoist C, Mathis D. 2007. Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J. Exp. Med. 204:112521–28
    [Google Scholar]
  126. 126. 
    Hubert FX, Kinkel SA, Davey GM, Phipson B, Mueller SN et al. 2011. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118:92462–72
    [Google Scholar]
  127. 127. 
    Skogberg G, Lundberg V, Berglund M, Gudmundsdottir J, Telemo E et al. 2015. Human thymic epithelial primary cells produce exosomes carrying tissue-restricted antigens. Immunol. Cell Biol. 93:8727–34
    [Google Scholar]
  128. 128. 
    Perry JSA, Russler-Germain EV, Zhou YW, Purtha W, Cooper ML et al. 2018. CD36 mediates cell-surface antigens to promote thymic development of the regulatory T cell receptor repertoire and allo-tolerance. Immunity 48:5923–36.e4
    [Google Scholar]
  129. 129. 
    Herbin O, Bonito AJ, Jeong S, Weinstein EG, Rahman AH et al. 2016. Medullary thymic epithelial cells and CD8α+ dendritic cells coordinately regulate central tolerance but CD8α+ cells are dispensable for thymic regulatory T cell production. J. Autoimmun. 75:141–49
    [Google Scholar]
  130. 130. 
    Perry JSA, Lio CWJ, Kau AL, Nutsch K, Yang Z et al. 2014. Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41:3414–26
    [Google Scholar]
  131. 131. 
    Bonasio R, Scimone ML, Schaerli P, Grabie N, Lichtman AH, von Andrian UH. 2006. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat. Immunol. 7:101092–100
    [Google Scholar]
  132. 132. 
    Hadeiba H, Lahl K, Edalati A, Oderup C, Habtezion A et al. 2012. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36:3438–50
    [Google Scholar]
  133. 133. 
    Proietto AI, Van Dommelen S, Zhou P, Rizzitelli A, D'Amico A et al. 2008. Dendritic cells in the thymus contribute to T-regulatory cell induction. PNAS 105:5019869–74
    [Google Scholar]
  134. 134. 
    Baba T, Nakamoto Y, Mukaida N. 2009. Crucial contribution of thymic Sirpα+ conventional dendritic cells to central tolerance against blood-borne antigens in a CCR2-dependent manner. J. Immunol. 183:53053–63
    [Google Scholar]
  135. 135. 
    Atibalentja DF, Murphy KM, Unanue ER. 2011. Functional redundancy between thymic CD8α+ and Sirpα+ conventional dendritic cells in presentation of blood-derived lysozyme by MHC class II proteins. J. Immunol. 186:31421–31
    [Google Scholar]
  136. 136. 
    Lopes N, Charaix J, Cédile O, Sergé A, Irla M. 2018. Lymphotoxin α fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells. Nat. Commun. 9:11262
    [Google Scholar]
  137. 137. 
    Lancaster JN, Thyagarajan HM, Srinivasan J, Li Y, Hu Z, Ehrlich LIR. 2019. Live-cell imaging reveals the relative contributions of antigen-presenting cell subsets to thymic central tolerance. Nat. Commun. 10:12220
    [Google Scholar]
  138. 138. 
    Atibalentja DF, Byersdorfer CA, Unanue ER. 2009. Thymus-blood protein interactions are highly effective in negative selection and regulatory T cell induction. J. Immunol. 183:127909–18
    [Google Scholar]
  139. 139. 
    Li J, Park J, Foss D, Goldschneider I. 2009. Thymus-homing peripheral dendritic cells constitute two of the three major subsets of dendritic cells in the steady-state thymus. J. Exp. Med. 206:3607–22
    [Google Scholar]
  140. 140. 
    Cédile O, Løbner M, Toft-Hansen H, Frank I, Wlodarczyk A et al. 2014. Thymic CCL2 influences induction of T-cell tolerance. J. Autoimmun. 55:173–85
    [Google Scholar]
  141. 141. 
    Cédile O, Jørgensen , Frank I, Wlodarczyk A, Owens T. 2017. The chemokine receptor CCR2 maintains plasmacytoid dendritic cell homeostasis. Immunol. Lett. 192:72–78
    [Google Scholar]
  142. 142. 
    Ennamorati M, Vasudevan C, Clerkin K, Halvorsen S, Verma S et al. 2020. Intestinal microbes influence development of thymic lymphocytes in early life. PNAS 117:52570–78
    [Google Scholar]
  143. 143. 
    Cebula A, Seweryn M, Rempala GA, Pabla SS, McIndoe RA et al. 2013. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature 497:7448258–62
    [Google Scholar]
  144. 144. 
    Oh J, Wu N, Barczak AJ, Barbeau R, Erle DJ, Shin J-S. 2018. CD40 mediates maturation of thymic dendritic cells driven by self-reactive CD4+ thymocytes and supports development of natural regulatory T cells. J. Immunol. 200:41399–412
    [Google Scholar]
  145. 145. 
    Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B et al. 2000. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12:4431–40
    [Google Scholar]
  146. 146. 
    Vang KB, Yang J, Pagán AJ, Li L-X, Wang J et al. 2010. Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. J. Immunol. 184:84074–77
    [Google Scholar]
  147. 147. 
    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. 6:2152–62
    [Google Scholar]
  148. 148. 
    Oh H, Grinberg-Bleyer Y, Liao W, Maloney D, Wang P et al. 2017. An NF-κB transcription-factor-dependent lineage-specific transcriptional program promotes regulatory T cell identity and function. Immunity 47:3450–65.e5
    [Google Scholar]
  149. 149. 
    Schuster M, Plaza-Sirvent C, Visekruna A, Huehn J, Schmitz I. 2019. Generation of Foxp3+CD25⁻ regulatory T-cell precursors requires c-Rel and IκBNS. Front. Immunol. 10:1583
    [Google Scholar]
  150. 150. 
    Fulford TS, Grumont R, Wirasinha RC, Ellis D, Barugahare A et al. 2021. c-Rel employs multiple mechanisms to promote the thymic development and peripheral function of regulatory T cells in mice. Eur. J. Immunol. 51:82006–26
    [Google Scholar]
  151. 151. 
    Isomura I, Palmer S, Grumont RJ, Bunting K, Hoyne G et al. 2009. c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J. Exp. Med. 206:133001–14
    [Google Scholar]
  152. 152. 
    Pobezinsky LA, Angelov GS, Tai X, Jeurling S, Van Laethem F et al. 2012. Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat. Immunol. 13:6569–78
    [Google Scholar]
  153. 153. 
    Watanabe M, Lu Y, Breen M, Hodes RJ. 2020. B7-CD28 co-stimulation modulates central tolerance via thymic clonal deletion and Treg generation through distinct mechanisms. Nat. Commun. 11:16264
    [Google Scholar]
  154. 154. 
    Breed ER, Watanabe M, Hogquist KA. 2019. Measuring thymic clonal deletion at the population level. J. Immunol. 202:113226–33
    [Google Scholar]
  155. 155. 
    Hikosaka Y, Nitta T, Ohigashi I, Yano K, Ishimaru N et al. 2008. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29:3438–50
    [Google Scholar]
  156. 156. 
    Spence PJ, Green EA. 2008. Foxp3+ regulatory T cells promiscuously accept thymic signals critical for their development. PNAS 105:3973–78
    [Google Scholar]
  157. 157. 
    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. 189:41717–25
    [Google Scholar]
  158. 158. 
    Walters SN, Webster KE, Daley S, Grey ST. 2014. A role for intrathymic B cells in the generation of natural regulatory T cells. J. Immunol. 193:1170–76
    [Google Scholar]
  159. 159. 
    Foy TM, Page DM, Waldschmidt TJ, Schoneveld A, Laman JD et al. 1995. An essential role for gp39, the ligand for CD40, in thymic selection. J. Exp. Med. 182:51377–88
    [Google Scholar]
  160. 160. 
    Williams JA, Sharrow SO, Adams AJ, Hodes RJ 2002. CD40 ligand functions non-cell autonomously to promote deletion of self-reactive thymocytes. J. Immunol. 168:62759–65
    [Google Scholar]
  161. 161. 
    Irla M, Guenot J, Sealy G, Reith W, Imhof BA, Sergé A. 2013. Three-dimensional visualization of the mouse thymus organization in health and immunodeficiency. J. Immunol. 190:2586–96
    [Google Scholar]
  162. 162. 
    Williams JA, Zhang J, Jeon H, Nitta T, Ohigashi I et al. 2014. Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways. J. Immunol. 192:2630–40
    [Google Scholar]
  163. 163. 
    Spidale NA, Wang B, Tisch R. 2014. Cutting edge: Antigen-specific thymocyte feedback regulates homeostatic thymic conventional dendritic cell maturation. J. Immunol. 193:121–25
    [Google Scholar]
  164. 164. 
    Fujihara C, Williams JA, Watanabe M, Jeon H, Sharrow SO, Hodes RJ. 2014. T cell-B cell thymic cross-talk: Maintenance and function of thymic B cells requires cognate CD40-CD40 ligand interaction. J. Immunol. 193:115534–44
    [Google Scholar]
  165. 165. 
    Yamano T, Nedjic J, Hinterberger M, Steinert M, Koser S et al. 2015. Thymic B cells are licensed to present self antigens for central T cell tolerance induction. Immunity 42:61048–61
    [Google Scholar]
  166. 166. 
    Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y et al. 2014. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat. Immunol. 15:5473–81
    [Google Scholar]
  167. 167. 
    Klinger M, Kim JK, Chmura SA, Barczak A, Erle DJ, Killeen N. 2009. Thymic OX40 expression discriminates cells undergoing strong responses to selection ligands. J. Immunol. 182:84581–89
    [Google Scholar]
  168. 168. 
    Hu DY, Wirasinha RC, Goodnow CC, Daley SR. 2017. IL-2 prevents deletion of developing T-regulatory cells in the thymus. Cell Death Differ 24:61007–16
    [Google Scholar]
  169. 169. 
    Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY 2005. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6:111142–51
    [Google Scholar]
  170. 170. 
    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. 181:53285–90
    [Google Scholar]
  171. 171. 
    Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. 2007. IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178:1280–90
    [Google Scholar]
  172. 172. 
    Soper DM, Kasprowicz DJ, Ziegler SF. 2007. IL-2Rβ links IL-2R signaling with Foxp3 expression. Eur. J. Immunol. 37:71817–26
    [Google Scholar]
  173. 173. 
    Malek TR, Yu A, Vincek V, Scibelli P, Kong L. 2002. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice: implications for the nonredundant function of IL-2. Immunity 17:2167–78
    [Google Scholar]
  174. 174. 
    Caramalho I, Nunes-Silva V, Pires AR, Mota C, Pinto AI et al. 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
    [Google Scholar]
  175. 175. 
    Yao Z, Kanno Y, Kerenyi M, Stephens G, Durant L et al. 2007. Nonredundant roles for Stat5a/b in directly regulating Foxp. Blood 109:104368–75
    [Google Scholar]
  176. 176. 
    Dikiy S, Li J, Bai L, Jiang M, Janke L et al. 2021. A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance. Immunity 54:5931–46.e11
    [Google Scholar]
  177. 177. 
    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. 16:6635–41
    [Google Scholar]
  178. 178. 
    Owen DL, Mahmud SA, Vang KB, Kelly RM, Blazar BR et al. 2018. Identification of cellular sources of IL-2 needed for regulatory T cell development and homeostasis. J. Immunol. 200:123926–33
    [Google Scholar]
  179. 179. 
    Konkel JE, Jin W, Abbatiello B, Grainger JR, Chen W 2014. Thymocyte apoptosis drives the intrathymic generation of regulatory T cells. PNAS 111:4E465–73
    [Google Scholar]
  180. 180. 
    Thiault N, Darrigues J, Adoue V, Gros M, Binet B et al. 2015. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nat. Immunol. 16:6628–34
    [Google Scholar]
  181. 181. 
    Cui G, Hara T, Simmons S, Wagatsuma K, Abe A et al. 2014. Characterization of the IL-15 niche in primary and secondary lymphoid organs in vivo. PNAS 111:51915–20
    [Google Scholar]
  182. 182. 
    Li MO, Sanjabi S, Flavell RAA 2006. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25:3455–71
    [Google Scholar]
  183. 183. 
    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-β receptor. Immunity 25:3441–54
    [Google Scholar]
  184. 184. 
    Diebold RJ, Eis MJ, Yin M, Ormsby I, Boivini GP et al. 1995. Early-onset multifocal inflammation in the transforming growth factor β1-null mouse is lymphocyte mediated. PNAS 92:2612215–19
    [Google Scholar]
  185. 185. 
    Ouyang W, Beckett O, Ma Q, Li MO 2010. Transforming growth factor-β signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32:5642–53
    [Google Scholar]
  186. 186. 
    Chen WJ, Jin W, Hardegen N, Lei KJ, Li L et al. 2003. Conversion of peripheral CD4+CD25⁻ naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198:121875–86
    [Google Scholar]
  187. 187. 
    Liu Y, Zhang P, Li J, Kulkarni AB, Perruche S, Chen WJ 2008. A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat. Immunol. 9:6632–40
    [Google Scholar]
  188. 188. 
    McCarron MJ, Irla M, Sergé A, Soudja SMH, Marie JC. 2019. Transforming growth factor-beta signaling in αβ thymocytes promotes negative selection. Nat. Commun. 10:15690
    [Google Scholar]
  189. 189. 
    Wang R, Zhang L, Zhang X, Moreno J, Celluzzi C et al. 2002. Regulation of activation-induced receptor activator of NF-κB ligand (RANKL) expression in T cells. Eur. J. Immunol. 32:41090–98
    [Google Scholar]
/content/journals/10.1146/annurev-immunol-101320-022432
Loading
/content/journals/10.1146/annurev-immunol-101320-022432
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error