Dormant pathogenic CD4+ T cells are prevalent in the peripheral repertoire of healthy mice

Anna Cebula,Grzegorz Rempala,Piotr Kraj,Wessam R Elhefnawy,Edyta Szurek,Michal Kuczma,Natasha Savage,Maciej Pietrzak,Leszek Ignatowicz

doi:10.1038/s41467-019-12820-3

Abstract

Thymic central tolerance eliminates most immature T cells with autoreactive T cell receptors (TCR) that recognize self MHC/peptide complexes. Regardless, an unknown number of autoreactive CD4+Foxp3− T cells escape negative selection and in the periphery require continuous suppression by CD4+Foxp3+ regulatory cells (Tregs). Here, we compare immune repertoires of Treg-deficient and Treg-sufficient mice to find Tregs continuously constraining one-third of mature CD4+Foxp3− cells from converting to pathogenic effectors in healthy mice. These dormant pathogenic clones frequently express TCRs activatable by ubiquitous autoantigens presented by class II MHCs on conventional dendritic cells, including self-peptides that select them in the thymus. Our data thus suggest that identification of most potentially autoreactive CD4+ T cells in the peripheral repertoire is critical to harness or redirect these cells for therapeutic advantage.

Highlights

Thymic central tolerance eliminates most immature T cells with autoreactive T cell receptors (TCR) that recognize self MHC/peptide complexes
The current paradigm proposes that in healthy individuals, peripheral CD4+ T cells rarely become autoreactive because most thymocytes expressing αβTCRs (TCRs) which bind self MHC/peptide complexes with moderate to high affinity are eliminated by thymic negative selection[1,2,3,4]
The identities of autoreactive CD4+ clones exclusive to the Sf strain versus those shared with healthy mice have not been investigated. This analysis can be achieved by comparing autoreactive TCRs on peripheral CD4+Foxp3− cells in Sf mice with TCRs expressed by cells with activated phenotype present in healthy mice

Summary

Introduction

Thymic central tolerance eliminates most immature T cells with autoreactive T cell receptors (TCR) that recognize self MHC/peptide complexes. We compare immune repertoires of Treg-deficient and Treg-sufficient mice to find Tregs continuously constraining one-third of mature CD4+Foxp3− cells from converting to pathogenic effectors in healthy mice These dormant pathogenic clones frequently express TCRs activatable by ubiquitous autoantigens presented by class II MHCs on conventional dendritic cells, including selfpeptides that select them in the thymus. 1234567890():,; The current paradigm proposes that in healthy individuals, peripheral CD4+ T cells rarely become autoreactive because most thymocytes expressing αβTCRs (TCRs) which bind self MHC/peptide complexes with moderate to high affinity are eliminated by thymic negative selection[1,2,3,4]. Finding potentially autoreactive CD4+ cells in healthy individuals is a challenging task because mechanisms of peripheral tolerance including anergy, expression of inhibitory co-receptors and suppression mediated by Tregs continuously sustain quiescence of self-reactive T cells. We propose that common selection by agonist self-peptides and limited intrathymic deletion enrich peripheral repertoire of CD4+Foxp3− cells in many dormant autoreactive clones that in suitable conditions can cause autoimmunity

Methods

Results

Conclusion