Thymic regulatory T cells arise via two distinct developmental programs

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / immunology
  • Cell Differentiation / immunology*
  • Colitis / immunology
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • 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 / physiology*
  • 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
  • T-Lymphocytes, Regulatory / physiology*
  • Thymus Gland / cytology
  • Thymus Gland / growth & development*
  • Thymus Gland / immunology


  • Autoantigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Il2ra protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • myelin oligodendrocyte glycoprotein (35-55)
  • Freund's Adjuvant