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

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.

Role of CNSs Conserved Distal Cis-Regulatory Elements in CD4 + T Cell Development and Differentiation

“…For example, vitamin C could enhance TET enzyme activity to increase Treg production ( 101 ). Other strategies could involve manipulating microbiota ( 76 ) and their metabolism to trigger CNS activity in gut CD4 + T cells and alleviate intestinal inflammation. Further, CRISPR-mediated knock-in, deletions, or chromatin editing at CNSs could help up-regulate important regulatory genes in CD4 + T cells and improve their effectiveness in adoptive transfer-based T cell therapies ( 118 ).…”

“…Hence, the microorganisms producing isoDCA promote iTreg generation, further linking the microbial metabolism to beneficial effects on immune homeostasis. However, Foxp3 CNS1 mutation could be compensated by increased induction of anergic (Tan) cells of mouse and subsequent conversion of Tan cells into iTreg cells promoted by commensal bacteria, thereby preventing gut inflammation and autoimmunity ( 76 ).…”

The Role of CD4+ T Cells and Microbiota in the Pathogenesis of Asthma

“…Members of the genus Akkermansia are gram-negative anaerobic bacteria that inhibit the development of asthma by promoting differentiation of Treg [ 106 ]. In a study by Kuczma et al, Akkermansia- derived antigenic peptide-induced anergy of T cells and increased the peripheral Treg population [ 107 ]. Michalovich et al showed that oral administration of A. muciniphila reduced OVA-induced eosinophilic inflammation [ 106 ].…”

Antigen‐driven CD4+ T‐cell anergy: a pathway to peripheral T regulatory cells

“…T regulatory cells (Tregs) and the induction of anergy in CD4 + T cells have both been implicated in the maintenance of peripheral tolerance to self‐antigens and mucosal antigens. In a recent study in Mucosal Immunology , Kuczma and colleagues 1 have further advanced the understanding of the relationship between T‐cell anergy and Tregs to both self‐antigens and mucosal antigens.…”

“…Kuczma et al . have identified novel epitopes from Akkermansia muciniphila , a commensal bacterium found in the gut, that are able to induce anergy 1,9 . Earlier this year, Kuczma et al .…”