Self and microbiota-derived epitopes induce CD4+ T cell anergy and conversion into CD4+Foxp3+ regulatory cells

Michal P Kuczma,Timothy L Denning,Edyta A Szurek,Vu L Ngo,Piotr Kraj,Maciej Pietrzak,Leszek Ignatowicz,Anna Cebula

doi:10.1038/s41385-020-00349-4

Michal P Kuczma, Timothy L Denning + Show 6 more

Open Access

https://doi.org/10.1038/s41385-020-00349-4

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Abstract

The physiological role of T cell anergy induction as a key mechanism supporting self-tolerance remains undefined, and natural antigens that induce anergy are largely unknown. In this report, we used TCR sequencing to show that the recruitment of CD4+CD44+Foxp3−CD73+FR4+ anergic (Tan) cells expands the CD4+Foxp3+ (Tregs) repertoire. Next, we report that blockade in peripherally-induced Tregs (pTregs) formation due to mutation in CNS1 region of Foxp3 or chronic exposure to a selecting self-peptide result in an accumulation of Tan cells. Finally, we show that microbial antigens from Akkermansia muciniphila commensal bacteria can induce anergy and drive conversion of naive CD4+CD44-Foxp3− T (Tn) cells to the Treg lineage. Overall, data presented here suggest that Tan induction helps the Treg repertoire to become optimally balanced to provide tolerance toward ubiquitous and microbiome-derived epitopes, improving host ability to avert systemic autoimmunity and intestinal inflammation.

Highlights

T cells anergy is a long-term, but reversible, state of unresponsiveness acquired by naive T cells (Tn) upon suboptimal activation by cognate MHC/peptide complexes that occurred in the absence of co-stimulatory signal[1]
We found that approximately half (42.6%) of the that express αβTCRs (TCRs) abundant on Tregs were expressed on CD4+Foxp3−FR4+CD73+ the recruitment of CD4+CD44+Foxp3−CD73+FR4+ anergic (Tan) cells, of which more than 60% were shared by transferred CD4+Foxp3−CD44− (Tn), Tan, and Treg subsets
We found that a transfer of exclusively CD4+CD44−Foxp3GFP− Tn cells from EpTCRmini mice to lymphopenic EpTCRαk/o recipients resulted in lethal cachexia in

Summary

Introduction

T cells anergy is a long-term, but reversible, state of unresponsiveness acquired by naive T cells (Tn) upon suboptimal activation by cognate MHC/peptide complexes that occurred in the absence of co-stimulatory signal[1]. Altered mTORC1 and Ras/MAPKs signaling in addition to NFAT homodimer formation are initial intracellular events that recruit histone deacetylases, activate Egr2/3, Sirt and Ikaros transcription factors and redistribute Cbl-b and Itch E3 ligases from the cytosol into endosomes. These changes repress cytokine production and expression of phospholipase C-γ1 and PKC-θ, which leads to proliferative arrest in anergic T cells[3,4]. Tregs absence prevents the induction of anergy in transferred, naive CD4+CD45RBhigh cells that become effectors activated by microbiota-derived antigens, and cause wasting disease. When lymphopenic mice receive an adoptive transfer of CD4+Foxp3− Tan cells, these recipients do not succumb to wasting disease because the fraction of the transferred subset has been already committed to converting to Tregs[5]

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