1. Thymic regulatory T cells arise via two distinct developmental programs.
- Author
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Owen DL, Mahmud SA, 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, and Farrar MA
- Subjects
- Animals, Autoantigens immunology, Colitis immunology, Disease Models, Animal, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Freund's Adjuvant administration & dosage, Freund's Adjuvant immunology, Humans, Immune Tolerance immunology, Interleukin-2 Receptor alpha Subunit metabolism, Lymphoid Progenitor Cells transplantation, Mice, Mice, Transgenic, Mycobacterium tuberculosis immunology, Myelin-Oligodendrocyte Glycoprotein administration & dosage, Myelin-Oligodendrocyte Glycoprotein immunology, Peptide Fragments administration & dosage, Peptide Fragments immunology, Signal Transduction, Specific Pathogen-Free Organisms, Thymus Gland cytology, Thymus Gland immunology, Cell Differentiation immunology, Encephalomyelitis, Autoimmune, Experimental immunology, Lymphoid Progenitor Cells physiology, T-Lymphocytes, Regulatory physiology, Thymus Gland growth & development
- 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 Treg cells were generated through two distinct developmental programs involving CD25+ Treg cell progenitors (CD25+ Treg P cells) and Foxp3lo Treg cell progenitors (Foxp3lo Treg P cells). CD25+ Treg P cells showed higher rates of apoptosis and interacted with thymic self antigens with higher affinity than did Foxp3lo Treg P cells, and had a T cell antigen receptor repertoire and transcriptome distinct from that of Foxp3lo Treg P cells. The development of both CD25+ Treg P cells and Foxp3lo Treg P cells was controlled by distinct signaling pathways and enhancers. Transcriptomics and histocytometric data suggested that CD25+ Treg P cells and Foxp3lo Treg P cells arose by coopting negative-selection programs and positive-selection programs, respectively. Treg cells derived from CD25+ Treg P cells, but not those derived from Foxp3lo Treg P 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.- Published
- 2019
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