A temporal thymic selection switch and ligand binding kinetics constrain neonatal Foxp3 + T reg cell development

Nat Immunol. 2019 Aug;20(8):1046-1058. doi: 10.1038/s41590-019-0414-1. Epub 2019 Jun 17.

Abstract

The neonatal thymus generates Foxp3+ regulatory T (tTreg) cells that are critical in controlling immune homeostasis and preventing multiorgan autoimmunity. The role of antigen specificity on neonatal tTreg cell selection is unresolved. Here we identify 17 self-peptides recognized by neonatal tTreg cells, and reveal ligand specificity patterns that include self-antigens presented in an age- and inflammation-dependent manner. Fate-mapping studies of neonatal peptidyl arginine deiminase type IV (Padi4)-specific thymocytes reveal disparate fate choices. Neonatal thymocytes expressing T cell receptors that engage IAb-Padi4 with moderate dwell times within a conventional docking orientation are exported as tTreg cells. In contrast, Padi4-specific T cell receptors with short dwell times are expressed on CD4+ T cells, while long dwell times induce negative selection. Temporally, Padi4-specific thymocytes are subject to a developmental stage-specific change in negative selection, which precludes tTreg cell development. Thus, a temporal switch in negative selection and ligand binding kinetics constrains the neonatal tTreg selection window.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoantigens / immunology*
  • Autoimmunity / immunology
  • Cell Differentiation / immunology
  • Cell Line
  • Female
  • Forkhead Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Protein-Arginine Deiminases / metabolism
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*
  • Self Tolerance / immunology*
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology
  • Thymus Gland / cytology

Substances

  • Autoantigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Antigen, T-Cell, alpha-beta
  • Padi4 protein, mouse
  • Protein-Arginine Deiminases