Regulatory T cells modulate presentation of autoantigens via pMHCII removal 4400

Abstract Description Regulatory T cells (Tregs) maintain immune tolerance through mechanisms activated by T cell receptor (TCR) antigen recognition. Tregs bind antigen-presenting cells (APCs) with high avidity and remove cognate peptide-Major Histocompatibility Complex Class II (pMHCII) via processes akin to trogocytosis and transendocytosis. This selective suppression spares APCs’ ability to present other antigens while inhibiting effector CD4+ T cells that recognize the same pMHCII as Tregs in vivo. However, whether this mechanism operates in human Tregs and its potential for antigen-specific therapies remain unclear. To address this, we generated TCR-transduced human Tregs specific for the autoantigen glutamic acid decarboxylase (GAD) 65 peptide 555-567, presented by APCs expressing the autoimmunity-associated allele HLA–DRB1*04:01 (HLA-DR4). We demonstrated that GAD65-specific Tregs capture antigen from peptide-loaded HLA-DR4+ B cells and monocytes. Importantly, pMHCII removal was enhanced in Tregs with higher TCR affinity, highlighting their therapeutic potential. To study unmodified antigen-specific memory Tregs, we developed a novel sorting and expansion pipeline for bona fide antigen-specific Tregs from human PBMCs. Expanded Tregs similarly captured cognate pMHCII from autologous APCs, providing the first evidence of this mechanism in human Tregs. These findings suggest pMHCII depletion is a fundamental mechanism by which antigen-specific Tregs modulate autoantigen presentation. Funding Sources NIH DP2AI15445 Topic Categories Therapeutic Approaches to Autoimmunity (THER)