An essential role for the IL-2 receptor in T reg cell function

Nature Immunology

Volumn 17, Issue 11, 2016, Pages 1322-1333

  Chinen, Takatoshi ^a,h   Kannan, Arun K ^b,g,h   Levine, Andrew G ^a   Fan, Xiying ^a   Klein, Ulf ^c,d   Zheng, Ye ^e   Gasteiger, Georg ^a,f   Feng, Yongqiang ^a   Fontenot, Jason D ^b,g   Rudensky, Alexander Y ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b BIOGEN   (United States)

^c Howard Hughes Medical Institute   (United States)

^d New York Presbyterian Morgan Stanley Children's Hospital   (United States)

^e SALK INSTITUTE FOR BIOLOGICAL STUDIES   (United States)

^f UNIVERSITY MEDICAL CENTER MAINZ   (Germany)

^g ABBVIE INC   (United States)

^h Exploratory Biology   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CRE RECOMBINASE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; INTERLEUKIN 15; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 2 RECEPTOR BETA; JANUS KINASE; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; STAT5 PROTEIN; STAT5B PROTEIN; TRANSCRIPTION FACTOR FOXP3; BIOLOGICAL MARKER; CYTOKINE;

ALLELE; ANIMAL CELL; ARTICLE; CD4+ T LYMPHOCYTE; CONTROLLED STUDY; FEMALE; GENE LOCUS; GENETIC GAIN; IN VIVO STUDY; LOSS OF FUNCTION MUTATION; LYMPHOCYTE FUNCTION; LYMPHOCYTE PROLIFERATION; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION; SUPPRESSOR CELL; ANIMAL; CD8+ T LYMPHOCYTE; GENETICS; IMMUNOLOGY; IMMUNOMODULATION; KNOCKOUT MOUSE; MALE; METABOLISM; PHENOTYPE; T LYMPHOCYTE SUBPOPULATION; TRANSGENIC MOUSE;

ANIMALS; BIOMARKERS; CD8-POSITIVE T-LYMPHOCYTES; CYTOKINES; FEMALE; IMMUNOMODULATION; MALE; MICE; MICE, KNOCKOUT; MICE, TRANSGENIC; PHENOTYPE; RECEPTORS, INTERLEUKIN-2; STAT5 TRANSCRIPTION FACTOR; T-LYMPHOCYTE SUBSETS; T-LYMPHOCYTES, REGULATORY;

EID: 84991678476     PISSN: 15292908     EISSN: 15292916     Source Type: Journal    
DOI: 10.1038/ni.3540     Document Type: Article

References (50)

1. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151-1164 (1995).
2. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057-1061 (2003).
3. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330-336 (2003).
4. Waldmann, T. A. The multi-subunit interleukin-2 receptor. Annu. Rev. Biochem. 58, 875-911 (1989).
5. Furtado, G. C., Curotto de Lafaille, M. A., Kutchukhidze, N. & Lafaille, J. J. Interleukin 2 signaling is required for CD4+ regulatory T cell function. J. Exp. Med. 196, 851-857 (2002).
6. Almeida, A. R., Legrand, N., Papiernik, M. & Freitas, A. A. Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J. Immunol. 169, 4850-4860 (2002).
7. 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).
8. 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).
9. Burchill, M. A., Yang, J., Vogtenhuber, C., Blazar, B. R. & Farrar, M. A. IL-2 receptor-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178, 280-290 (2007).
10. Yao, Z. et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109, 4368-4375 (2007).
11. Malek, T. R. & Bayer, A. L. Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 4, 665-674 (2004).
12. 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).
13. 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).
14. Malin, S. et al. Role of STAT5 in controlling cell survival and immunoglobulin gene recombination during pro-B cell development. Nat. Immunol. 11, 171-179 (2010).
15. Barron, L. et al. Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J. Immunol. 185, 6426-6430 (2010).
16. Setoguchi, R., Hori, S., Takahashi, T. & Sakaguchi, S. Homeostatic maintenance of natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 201, 723-735 (2005).
17. Rubtsov, Y. P. et al. Stability of the regulatory T cell lineage in vivo. Science 329, 1667-1671 (2010).
18. Komatsu, N. et al. Heterogeneity of natural Foxp3+ T cells: A committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl. Acad. Sci. USA 106, 1903-1908 (2009).
19. Hori, S. Lineage stability and phenotypic plasticity of Foxp3+ regulatory T cells. Immunol. Rev. 259, 159-172 (2014).
20. 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).
21. Thornton, A. M., Donovan, E. E., Piccirillo, C. A. & Shevach, E. M. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J. Immunol. 172, 6519-6523 (2004).
22. 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).
23. 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).
24. Yamaguchi, T. et al. Construction of self-recognizing regulatory T cells from conventional T cells by controlling CTLA-4 and IL-2 expression. Proc. Natl. Acad. Sci. USA 110, E2116-E2125 (2013).
25. Smigiel, K. S. et al. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J. Exp. Med. 211, 121-136 (2014).
26. Zambrowicz, B. P. et al. Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of-galactosidase in mouse embryos and hematopoietic cells. Proc. Natl. Acad. Sci. USA 94, 3789-3794 (1997).
27. Onishi, M. et al. Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation. Mol. Cell. Biol. 18, 3871-3879 (1998).
28. 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).
29. Chen, Y. et al. Foxp3+ regulatory T cells promote T helper 17 cell development in vivo through regulation of interleukin-2. Immunity 34, 409-421 (2011).
30. Cong, Y., Feng, T., Fujihashi, K., Schoeb, T. R. & Elson, C. O. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc. Natl. Acad. Sci. USA 106, 19256-19261 (2009).
31. Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191-197 (2007).
32. Su, L. K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668-670 (1992).
33. Arvey, A. et al. Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells. Nat. Immunol. 15, 580-587 (2014).
34. Levine, A. G., Arvey, A., Jin, W. & Rudensky, A. Y. Continuous requirement for the TCR in regulatory T cell function. Nat. Immunol. 15, 1070-1078 (2014).
35. Vahl, J. C. et al. Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity 41, 722-736 (2014).
36. Tadokoro, C. E. et al. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J. Exp. Med. 203, 505-511 (2006).
37. Lio, C. W. & Hsieh, C. S. A two-step process for thymic regulatory T cell development. Immunity 28, 100-111 (2008).
38. Feng, Y. et al. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158, 749-763 (2014).
39. Tran, D. Q. et al. Analysis of adhesion molecules, target cells, and role of IL-2 in human FOXP3+ regulatory T cell suppressor function. J. Immunol. 182, 2929-2938 (2009).
40. Rudra, D. et al. Runx-CBFbeta complexes control expression of the transcription factor Foxp3 in regulatory T cells. Nat. Immunol. 10, 1170-1177 (2009).
41. Sojka, D. K., Bruniquel, D., Schwartz, R. H. & Singh, N. J. IL-2 secretion by CD4+ T cells in vivo is rapid, transient, and influenced by TCR-specific competition. J. Immunol. 172, 6136-6143 (2004).
42. Shanmugasundaram, R. & Selvaraj, R. K. Regulatory T cell properties of chicken CD4+CD25+ cells. J. Immunol. 186, 1997-2002 (2011).
43. Andersen, K. G., Nissen, J. K. & Betz, A. G. Comparative genomics reveals key gain-of-function events in Foxp3 during regulatory T cell evolution. Front. Immunol. 3, 113 (2012).
44. Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546-558 (2008).
45. Anders, S. et al. Count-based differential expression analysis of RNA sequencing data using R and Bioconductor. Nat. Protoc. 8, 1765-1786 (2013).
46. Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: A flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114-2120 (2014).
47. Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
48. Tarca, A. L. et al. A novel signaling pathway impact analysis. Bioinformatics 25, 75-82 (2009).
49. Maere, S., Heymans, K. & Kuiper, M. BiNGO: A Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 21, 3448-3449 (2005).
50. Merico, D., Isserlin, R., Stueker, O., Emili, A. & Bader, G. D. Enrichment map: A network-based method for gene-set enrichment visualization and interpretation. PLoS One 5, e13984 (2010).