Regulatory T Cells Act as Tolerogenic Antigen Presenting Cells to Suppress Autoimmunity 2310009

Introduction Professional antigen presenting cells (APC) initiate most T cell responses, but human T cells express MHC-II post-activation and present antigen, which studies indicate is tolerogenic. Tregs are immunosuppressive and have a higher activation status than conventional T cells (Tcons) and may therefore be a more potent tolerogenic APC. We used human cell culture and transgenic animal models to investigate the capability of Tregs and Tcons to present antigen and the resulting effect on responder T cells and autoimmunity. Methods Antigen-pulsed human APC T cells were cultured with antigen-specific responder T cells, proliferation and activation measured by flow cytometry and responders profiled by sequencing. Parallel mouse assays were performed using OVA-presenting MHC-II+ T cells from Lck-CIITA mice with OT-II T cells. APC function was evaluated in vivo in experimental autoimmune encephalomyelitis (EAE) by transferring Lck-CIITA Tcons or Tregs presenting MOG35—55 before disease induction with the same peptide and by targeting the peptide to Tregs for presentation with a Treg-specific IL-2—MOG fusion protein. Results Human Tregs from blood exhibited a more APC-like phenotype than Tcons, expressing higher levels of MHC-II and costimulatory molecules. In culture, all T cell subsets drove antigen-specific proliferation, but the response induced by Tregs was the most robust. In mouse culture, CD8+ Tcons and Tregs generated a proliferative response and promoted Foxp3 expression in responder cells. In vivo, treatment with CD4+ Tcons or Tregs presenting MOG prevented EAE, but only Treg APCs converted MOG-specific T cells into Tregs. Targeting of MOG to Tregs during disease onset using a Treg-specific IL-2 also ameliorated EAE. Conclusion From human data, we conclude that Tregs are functional APCs and in mouse models we find that they drive a tolerogenic response. These findings identify Treg antigen presentation as a novel mechanism of immune suppression that may be harnessed for treatment of autoimmunity.