Alloantigen‐specific regulatory T cells prevent experimental chronic graft‐versus‐host disease by simultaneous control of allo‐ and autoreactivity

Chronic graft‐versus‐host disease (c GVHD ) is characterised by a complex etiology of both alloimmune‐ and autoimmune‐mediated disease progression and pathology, and is consequently difficult to control. The therapeutic potential of regulatory T ( T reg) cells for c GVHD is currently being investigated; however, the relative ability of T reg cells with defined antigen specificities for auto‐ and alloantigen to prevent disease has not been previously examined. In this study, we show that donor‐derived T reg‐cell lines generated with self‐ MHC H ‐2 b specificity or specificity for BALB /c H ‐2 d alloantigen presented via the direct or indirect pathways are able to mediate an equal protection against c GVHD immune pathology in a disease model associated with recipient B ‐cell‐driven humoral autoimmunity and glomerulonephritis. Mechanistically, autospecific T reg cells prevented disease induction by blocking donor T ‐cell engraftment whereas allospecific T reg cells permitted long‐term engraftment of donor T cells. Donor T cells, while unresponsive to auto‐ and recipient alloantigens, retained the capacity to respond to third party alloantigens on ex vivo stimulation. These findings indicate that allospecific Treg cells may therefore be more clinically relevant as a cell therapy for c GVHD in the context of haplo‐identical hematopoietic transplantation, as they allow persistence of donor T cells capable of responding to foreign antigens whilst preventing c GVHD ‐mediated autoimmunity.