Thymic regulatory T cells arise via two distinct developmental programs

Owen, David L., Mahmud, Shawn A., Sjaastad, Louisa E., Williams, Jason B., Spanier, Justin A., Simeonov, Dimitre R., Ruscher, Roland, Huang, Weishan, Miller, Corey, Hekim, Can, Jeschkle, Jonathan C., Aggarwal, Praful, Broeckel, Ulrich, LaRue, Rebecca S., Henzler, Christine M., Alegre, Maria-Luisa, Anderson, Mark S., August, Avery, Marson, Alexander, Zheng, Ye, Williams, Calvin B., and Farrar, Michael A. (2019) Thymic regulatory T cells arise via two distinct developmental programs. Nature Immunology, 20. pp. 195-205.

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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 developmentalprograms that are both required for a comprehensive Treg cell repertoire capable of establishing immunotolerance.

Item ID: 57854
Item Type: Article (Research - C1)
ISSN: 1529-2916
Funders: University of Minnesota (UM), National Institutes of Health, Children's Hospital of Wisconsin
Projects and Grants: NIH F30DK096844, UM F0030624, NIH 5U24AI107027, NIH R01AI085090-07A1, NIH DP3DK111914-01, NIH R01AI115716
Date Deposited: 04 Apr 2019 00:46
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110704 Cellular Immunology @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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