Thymic regulatory T cells arise via two distinct developmental programs
Open accessAbstract
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.
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The two distinct developmental programs for tTreg cells are both required for the generation of a comprehensive Treg cell repertoire.
“Recent data suggest that the two distinct developmental programs are both required for the generation of a comprehensive Treg cell repertoire [442].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [442]
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Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)
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- Authors
- Owen, D. L., Mahmud, S. A., Sjaastad, L. E., Williams, J. B., Spanier, J. A., Simeonov, D. R., Ruscher, R., Huang, W., Proekt, I., Miller, C. N., Hekim, C., Jeschke, J. C., Aggarwal, P., Broeckel, U., LaRue, R. S., Henzler, C. M., Alegre, M.-L., Anderson, M. S., August, A., Marson, A., Zheng, Y., Williams, C. B., & Farrar, M. A.
- Affiliations
- University of Minnesota (US)
- Medical College of Wisconsin (US)
- University of California, San Francisco (US)
- Louisiana State University (US)
- University of Chicago (US)
- Cornell University (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Farrar, Michael A.
- ORCID
- Owen, David L.
- Mahmud, Shawn A.
- 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.
- 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.
- Venue
- Nature Immunology
- Published
- 2019-01-14
- Volume
- 20
- Issue
- 2
- Pages
- 195-205
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC6650268
- OpenAlex
- W2909310282
- Cited by
- 225
- References
- 57
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 26 · 2023: 30 · 2022: 38 · 2021: 41 · 2020: 33 · 2019: 16 · 2018: 1
- FWCI
- 12.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ResearchOnline at James Cook University (James Cook University) (submittedVersion)
- Civil War Book Review (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (5r01ai085090-10)
- National Cancer Institute (R01CA154998, R01CA185062, R01CA151845, P30CA014195, P30CA077598)
- National Institute of General Medical Sciences (P30GM110760, T32GM008568)
- National Institute of Allergy and Infectious Diseases (R01-AI-085090, R01AI115716, T32AI007334, R56AI061165, R21AI126814, R01AI061165, R56AI113138, R01AI107027, U24AI118635, R21AI108958, R01AI106791, R01AI120701, R21AI129422, P01AI097113, R37AI097457, T32AI007313, R01AI124512, P01AI035296)
- National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK111914, F30DK096844, P30DK042086)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- regulatory T cells, negative selection, positive selection, self-tolerance, experimental autoimmune encephalitis, immune tolerance, apoptosis, enhancer regulation
- MeSH terms
- Animals, Autoantigens, Cell Differentiation, Colitis, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Freund's Adjuvant, Humans, Immune Tolerance, Mice, Transgenic, Mycobacterium tuberculosis, Peptide Fragments, Specific Pathogen-Free Organisms, Thymus Gland, Signal Transduction, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Interleukin-2 Receptor alpha Subunit, Lymphoid Progenitor Cells, Myelin-Oligodendrocyte Glycoprotein
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