The developmental programs that generate a broad repertoire of regulatory T cells (T reg cells) able to respond to both self antigens and non-self antigens remain unclear. Here we found that mature T reg cells were generated through two distinct developmental programs involving CD25 + T reg cell progenitors (CD25 + T reg P cells) and Foxp3 lo T reg cell progenitors (Foxp3 lo T reg P cells). CD25 + T reg P cells showed higher rates of apoptosis and interacted with thymic self antigens with higher affinity than did Foxp3 lo T reg P cells, and had a T cell antigen receptor repertoire and transcriptome distinct from that of Foxp3 lo T reg P cells. The development of both CD25 + T reg P cells and Foxp3 lo T reg P cells was controlled by distinct signaling pathways and enhancers. Transcriptomics and histocytometric data suggested that CD25 + T reg P cells and Foxp3 lo T reg P cells arose by coopting negative-selection programs and positive-selection programs, respectively. T reg cells derived from CD25 + T reg P cells, but not those derived from Foxp3 lo T reg P cells, prevented experimental autoimmune encephalitis. Our findings indicate that T reg cells arise through two distinct developmental programs that are both required for a comprehensive T reg cell repertoire capable of establishing immunotolerance.
Bibliographical noteFunding Information:
We thank G. Hubbard, A. Rost, A. Meskic, D. Duerre and H. Wiesolek for technical assistance; T. Martin, N. Shah, J. Motl and P. Champoux for cell sorting and maintenance of the Flow Cytometry Core Facility at the University of Minnesota (5P01AI035296); S. Hamilton, M. Pierson and funding from the University of Minnesota academic health center for maintaining the NME mouse facility; P. Fink for providing initial Rag2-GFP thymi; B. Burbach and Y. Shimizu for Adap–/– mice; M. Jenkins for the MOG: I-Ab tetramer; and C. Katerndahl and L. Heltemes-Harris for helpful commentary and reviewing the manuscript. D.L.O. and S.A.M. were supported by an immunology training grant (no. 2T32AI007313). S.A.M. was also supported by an individual predoctoral F30 fellowship from the National Institutes of Health (NIH; no. F30DK096844). J.A.S. was supported by University of Minnesota Medical Foundation grant no. UMF0020624 and NIH grants nos 5U24AI118635 and R01AI106791. Y.Z. was supported by NIH grant no. R01AI107027. U.B. and C.B.W. were supported by grants from the Children’s Hospital of Wisconsin, and C.B.W. was also supported by NIH grant no. R01AI085090-07A1. A.M. and M.S.A were supported by NIH grant no. DP3DK111914-01. A.M. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund and is an investigator at the Chan Zuckerberg Biohub. M.A. was supported by NIH grant no. R01AI115716. M.S.A. was supported by NIH grant no. R37 AI097457. A.A. was supported by NIH grants nos AI108958, AI120701, AI126814 and AI129422 to A.A. and W.H. W.H. was supported by NIH grant no. AI29422 (to W.H. and A.A.), a Careers in Immunology Fellowship from the American Association of Immunologists, a Faculty Development Award and a competitive research grant from Louisiana State University, and a pilot award from the LSU-Tulane Center for Experimental Infectious Diseases Research funded by NIH grant no. GM110760. M.A.F. was supported by NIH grants nos AI124512, AI113138, AI061165, CA154998, CA151845 and CA185062.
A.M. is a co-founder of Spotlight Therapeutics. A.M. has served as an advisor to Juno Therapeutics and is a member of the scientific advisory board at PACT Pharma. The Marson laboratory has received sponsored research support from Juno Therapeutics, Epinomics and Sanofi, and a gift from Gilead. A.A. has received sponsored research support from 3M. MAF has received sponsored research support from Merck.
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