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Nat Immunol. 2019 Feb;20(2):195-205. doi: 10.1038/s41590-018-0289-6. Epub 2019 Jan 14.

Thymic regulatory T cells arise via two distinct developmental programs.

Author information

1
Center for Immunology, Masonic Cancer Center, and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
2
Section of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
3
Center for Immunology, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
4
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
5
Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
6
Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.
7
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
8
Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA.
9
Section of Genomic Pediatrics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
10
Supercomputing Institute for Advanced Computational Research, University of Minnesota, Minneapolis, MN, USA.
11
Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL, USA.
12
Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
13
Chan Zuckerberg Biohub, San Francisco, San Francisco, CA, USA.
14
Innovative Genomics Institute, University of California, Berkeley, CA, USA.
15
Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA, USA.
16
Center for Immunology, Masonic Cancer Center, and the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. farra005@umn.edu.

Abstract

The developmental programs that generate a broad repertoire of regulatory T cells (Treg cells) able to respond to both self antigens and non-self antigens remain unclear. Here we found that mature Treg cells were generated through two distinct developmental programs involving CD25+ Treg cell progenitors (CD25+ TregP cells) and Foxp3lo Treg cell progenitors (Foxp3lo TregP cells). CD25+ TregP cells showed higher rates of apoptosis and interacted with thymic self antigens with higher affinity than did Foxp3lo TregP cells, and had a T cell antigen receptor repertoire and transcriptome distinct from that of Foxp3lo TregP cells. The development of both CD25+ TregP cells and Foxp3lo TregP cells was controlled by distinct signaling pathways and enhancers. Transcriptomics and histocytometric data suggested that CD25+ TregP cells and Foxp3lo TregP cells arose by coopting negative-selection programs and positive-selection programs, respectively. Treg cells derived from CD25+ TregP cells, but not those derived from Foxp3lo TregP cells, prevented experimental autoimmune encephalitis. Our findings indicate that Treg cells arise through two distinct developmental programs that are both required for a comprehensive Treg cell repertoire capable of establishing immunotolerance.

PMID:
30643267
PMCID:
PMC6650268
DOI:
10.1038/s41590-018-0289-6
[Indexed for MEDLINE]
Free PMC Article

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