Thymic regulatory T cells arise via two distinct developmental programs

David L. Owen, Shawn Mahmud, Louisa E. Sjaastad, Jason B. Williams, Justin A Spanier, Dimitre R. Simeonov, Roland Ruscher, Weishan Huang, Irina Proekt, Corey N. Miller, Can Hekim, Jonathan C. Jeschke, Praful Aggarwal, Ulrich Broeckel, Rebecca S LaRue, Christine M. Henzler, Maria Luisa Alegre, Mark S. Anderson, Avery August, Alexander MarsonYe Zheng, Calvin B. Williams, Michael A Farrar

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)195-205
Number of pages11
JournalNature immunology
Volume20
Issue number2
DOIs
StatePublished - Feb 1 2019

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Regulatory T-Lymphocytes
Autoantigens
Stem Cells
T-Cell Antigen Receptor
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Thymic regulatory T cells arise via two distinct developmental programs. / Owen, David L.; Mahmud, Shawn; Sjaastad, Louisa E.; Williams, Jason B.; Spanier, Justin A; Simeonov, Dimitre R.; Ruscher, Roland; Huang, Weishan; Proekt, Irina; Miller, Corey N.; Hekim, Can; Jeschke, 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.; Farrar, Michael A.

In: Nature immunology, Vol. 20, No. 2, 01.02.2019, p. 195-205.

Research output: Contribution to journalArticle

Owen, DL, Mahmud, S, Sjaastad, LE, Williams, JB, Spanier, JA, Simeonov, DR, Ruscher, R, Huang, W, Proekt, I, Miller, CN, Hekim, C, Jeschke, JC, Aggarwal, P, Broeckel, U, LaRue, RS, Henzler, CM, Alegre, ML, Anderson, MS, August, A, Marson, A, Zheng, Y, Williams, CB & Farrar, MA 2019, 'Thymic regulatory T cells arise via two distinct developmental programs', Nature immunology, vol. 20, no. 2, pp. 195-205. https://doi.org/10.1038/s41590-018-0289-6
Owen, David L. ; Mahmud, Shawn ; Sjaastad, Louisa E. ; Williams, Jason B. ; Spanier, Justin A ; Simeonov, Dimitre R. ; Ruscher, Roland ; Huang, Weishan ; Proekt, Irina ; Miller, Corey N. ; Hekim, Can ; Jeschke, 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. ; Farrar, Michael A. / Thymic regulatory T cells arise via two distinct developmental programs. In: Nature immunology. 2019 ; Vol. 20, No. 2. pp. 195-205.
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