Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition

Nature Immunology

Volumn 16, Issue 6, 2015, Pages 635-641

  Weist, Brian M ^a   Kurd, Nadia ^a   Boussier, Jeremy ^b,c   Chan, Shiao Wei ^a   Robey, Ellen A ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b ECOLE NORMALE SUPÉRIEURE   (France)

^c INSTITUT PASTEUR   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIGEN; INTERLEUKIN 2; PEPTIDE; PROTEIN; T LYMPHOCYTE RECEPTOR; LYMPHOCYTE ANTIGEN RECEPTOR;

ANTIGEN PRESENTING CELL; ARTICLE; CELL MATURATION; CONTROLLED STUDY; DENDRITIC CELL; FEEDBACK SYSTEM; MOLECULAR RECOGNITION; NEGATIVE FEEDBACK; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; THYMOCYTE; TISSUE SLICE; UPREGULATION; AGONISTS; ANIMAL; ANTIGEN PRESENTATION; C57BL MOUSE; CELL DIFFERENTIATION; CELL LINE; GENETICS; IMMUNOLOGY; MOUSE; PHYSIOLOGY; THYMUS; TRANSGENIC MOUSE; TUMOR MICROENVIRONMENT;

ANIMALS; ANTIGEN PRESENTATION; ANTIGENS; CELL DIFFERENTIATION; CELL LINE; CELLULAR MICROENVIRONMENT; DENDRITIC CELLS; FEEDBACK, PHYSIOLOGICAL; INTERLEUKIN-2; MICE; MICE, INBRED C57BL; MICE, TRANSGENIC; RECEPTORS, ANTIGEN, T-CELL; T-LYMPHOCYTES, REGULATORY; THYMUS GLAND;

EID: 84929950085     PISSN: 15292908     EISSN: 15292916     Source Type: Journal    
DOI: 10.1038/ni.3171     Document Type: Article

References (49)

1. Asano, M. , Toda, M. , Sakaguchi, N. & Sakaguchi, S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 184, 387-396 (1996).
2. 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. 162, 5317-5326 (1999).
3. Sawant, D. V. & Vignali, D. A. Once a Treg, always a Treg? Immunol. Rev. 259, 173-191 (2014).
4. Riley, J. L. , June, C. H. & Blazar, B. R. Human T regulatory cell therapy: take a billion or so and call me in the morning. Immunity 30, 656-665 (2009).
5. von Boehmer, H. & Daniel, C. Therapeutic opportunities for manipulating TReg cells in autoimmunity and cancer. Nat. Rev. Drug Discov. 12, 51-63 (2013).
6. Burchill, M. A. et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 28, 112-121 (2008).
7. Lio, C. W. & Hsieh, C. S. A two-step process for thymic regulatory T cell development. Immunity 28, 100-111 (2008).
8. Moran, A. E. & Hogquist, K. A. T-cell receptor affinity in thymic development. Immunology 135, 261-267 (2012).
9. Jordan, M. S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2, 301-306 (2001).
10. Bautista, J. L. et al. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat. Immunol. 10, 610-617 (2009).
11. Leung, M. W. , Shen, S. & Lafaille, J. J. TCR-dependent differentiation of thymic Foxp3+ cells is limited to small clonal sizes. J. Exp. Med. 206, 2121-2130 (2009).
12. Granucci, F. et al. Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nat. Immunol. 2, 882-888 (2001).
13. Kulhankova, K. , Rouse, T. , Nasr, M. E. & Field, E. H. Dendritic cells control CD4+CD25+ Treg cell suppressor function in vitro through juxtacrine delivery of IL-2. PLoS ONE 7, e43609 (2012).
14. Vang, K. B. et al. IL-2,-7, and-15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development. J. Immunol. 181, 3285-3290 (2008).
15. Bayer, A. L. , Yu, A. , Adeegbe, D. & Malek, T. R. Essential role for interleukin-2 for CD4+ CD25+ T regulatory cell development during the neonatal period. J. Exp. Med. 201, 769-777 (2005).
16. Fontenot, J. D. , Rasmussen, J. P. , Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142-1151 (2005).
17. Lee, H. M. , Bautista, J. L. , Scott-Browne, J. , Mohan, J. F. & Hsieh, C. S. A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity 37, 475-486 (2012).
18. Atibalentja, D. F. , Byersdorfer, C. A. & Unanue, E. R. Thymus-blood protein interactions are highly effective in negative selection and regulatory T cell induction. J. Immunol. 183, 7909-7918 (2009).
19. Oh, J. et al. MARCH1-mediated MHCII ubiquitination promotes dendritic cell selection of natural regulatory T cells. J. Exp. Med. 210, 1069-1077 (2013).
20. Chen, W. et al. Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF induction of transcription factor Foxp3. J. Exp. Med. 198, 1875-1886 (2003).
21. Yadav, M. et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J. Exp. Med. 209, 1713-1722 (2012).
22. Weiss, J. M. et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med. 209, 1723-1742 (2012).
23. Kurts, C. et al. Constitutive class I-restricted exogenous presentation of self antigens in vivo. J. Exp. Med. 184, 923-930 (1996).
24. Olivares-Villagómez, D. , Wang, Y. & Lafaille, J. J. Regulatory CD4+ T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis. J. Exp. Med. 188, 1883-1894 (1998).
25. Cederbom, L. , Hall, H. & Ivars, F. CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur. J. Immunol. 30, 1538-1543 (2000).
26. Boyman, O. , Kovar, M. , Rubinstein, M. P. , Surh, C. D. & Sprent, J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311, 1924-1927 (2006).
27. Webster, K. E. 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. 206, 751-760 (2009).
28. Pandiyan, P. , Zheng, L. , Ishihara, S. , Reed, J. & Lenardo, M. J. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat. Immunol. 8, 1353-1362 (2007).
29. de la Rosa, M. , Rutz, S. , Dorninger, H. & Scheffold, A. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34, 2480-2488 (2004).
30. Gillis, S. & Smith, K. A. Long term culture of tumour-specific cytotoxic T cells. Nature 268, 154-156 (1977).
31. Boyman, O. & Sprent, J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat. Rev. Immunol. 12, 180-190 (2012).
32. Perry, J. S. et al. Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41, 414-426 (2014).
33. Proietto, A. I. et al. Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc. Natl. Acad. Sci. USA 105, 19869-19874 (2008).
34. Malek, T. R. , Yu, A. , Vincek, V. , Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2R-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167-178 (2002).
35. Román, E. , Shino, H. , Qin, F. X. & Liu, Y. J. Cutting edge: Hematopoietic-derived APCs select regulatory T cells in thymus. J. Immunol. 185, 3819-3823 (2010).
36. Aschenbrenner, K. et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol. 8, 351-358 (2007).
37. Hinterberger, M. et al. Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance. Nat. Immunol. 11, 512-519 (2010).
38. Sansom, S. N. et al. 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, 1918-1931 (2014).
39. Koble, C. & Kyewski, B. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med. 206, 1505-1513 (2009).
40. Busse, D. et al. Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments. Proc. Natl. Acad. Sci. USA 107, 3058-3063 (2010).
41. Kim, H. P. , Kelly, J. & Leonard, W. J. The basis for IL-2-induced IL-2 receptor chain gene regulation: importance of two widely separated IL-2 response elements. Immunity 15, 159-172 (2001).
42. Barthlott, T. et al. CD25+CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production. Int. Immunol. 17, 279-288 (2005).
43. Coquet, J. M. et al. Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway. J. Exp. Med. 210, 715-728 (2013).
44. Mahmud, S. A. et al. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat. Immunol. 15, 473-481 (2014).
45. Mamalaki, C. et al. Thymic depletion and peripheral activation of class I major histocompatibility complex-restricted T cells by soluble peptide in T-cell receptor transgenic mice. Proc. Natl. Acad. Sci. USA 89, 11342-11346 (1992).
46. Dzhagalov, I. L. , Melichar, H. J. , Ross, J. O. , Herzmark, P. & Robey, E. A. in Current Protocols in Cytometry (ed. , Robinson, J. P. ) Ch 12, 12. 26. 1-12. 26. 20 (John Wiley and Sons, 2012).
47. Melichar, H. J. , Ross, J. O. , Herzmark, P. , Hogquist, K. A. & Robey, E. A. Distinct temporal patterns of T cell receptor signaling during positive versus negative selection in situ. Sci. Signal. 6, ra92 (2013).
48. Ehrlich, L. I. , Oh, D. Y. , Weissman, I. L. & Lewis, R. S. Differential contribution of chemotaxis and substrate restriction to segregation of immature and mature thymocytes. Immunity 31, 986-998 (2009).
49. Halkias, J. et al. Opposing chemokine gradients control human thymocyte migration in situ. J. Clin. Invest. 123, 2131-2142 (2013).