Engineered antigen-specific T regulatory cells suppress autoreactivity to the anti-glomerular basement membrane disease antigen

Abstract

Anti-glomerular basement membrane (anti-GBM) disease is accompanied by insufficient antigen-specific regulatory T cells (Tregs) and clonally expanded antigen-specific conventional T cells. In particular, this applied to the immunodominant T cell autoepitope of type IV collagen, α3(IV)NC1_135-145, presented by human leukocyte antigen-DRB1∗1501. Here, we investigated whether Tregs engineered to express GBM-T cell receptors (TCR) specific for α3(IV)NC1_135-145 better suppress autoimmunity. The GBM-TCR Treg cell product exhibited a phenotypically stable Treg phenotype, produced α3(IV)NC1_135-145-specific functional responses, and were superior suppressors of autoreactive conventional T cells and bystander conventional T cells compared to polyclonal Tregs or irrelevant TCR-transduced Tregs. We also found that GBM-TCR Tregs modulate other immune cells like dendritic cells and B cells to a more tolerogenic phenotype. Importantly, our findings support the development of GBM-TCR Tregs as a promising cell-based therapy for anti-GBM disease.

Keywords: T-cell receptor (TCR); anti–glomerular basement membrane (GBM) disease; autoimmune disease; cell therapy; glomerulonephritis (GN); regulatory T cell (Treg).