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Nat Immunol. 2019 Jun 17. doi: 10.1038/s41590-019-0414-1. [Epub ahead of print]

A temporal thymic selection switch and ligand binding kinetics constrain neonatal Foxp3+ Treg cell development.

Author information

1
Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.
2
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
3
Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA. Eric.Huseby@umassmed.edu.

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.

PMID:
31209405
DOI:
10.1038/s41590-019-0414-1

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