Human gut microbiota–reactive DP8α Tregs prevent acute graft-versus-host disease in a CD73-dependent manner

Abstract

Graft-versus-host disease (GvHD) is a life-threatening complication frequently occurring following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Since gut microbiota and regulatory T cells (Tregs) are believed to play roles in GvHD prevention, we investigated whether DP8a Tregs, which we have previously described to harbor a TCR-specificity for the gut commensal Faecalibacterium prausnitzii, could protect against GvHD, thereby linking microbiota and its effect on GvHD. We observed a decrease in CD73 + DP8a Treg frequency in allo-HSCT patients at 1-month post-transplantation, which was associated with aGvHD development at 1-month post-transplantation, as compared to aGvHD-free patients, without being correlated to hematological disease's relapse. Importantly, CD73 activity was shown to be critical for DP8a Treg suppressive function. Moreover, the frequency of host-reactive DP8aTregs was also lower in aGvHD patients, as compared to aGvHD-free patients, which could embody a protective mechanism responsible for the maintenance of these cell subset in GvHD-free patients. We also showed that human DP8a Tregs protected mice against xeno-GvHD through limiting deleterious inflammation and preserving gut integrity. Altogether, these results demonstrated that human DP8a Tregs mediate aGvHD prevention in a CD73dependent manner, likely through host-reactivity, advocating for the use of these cells for the development of innovative therapeutic strategies to preclude aGvHD-related inflammation.