Targeting cell-surface VISTA expression on allospecific naïve T cells promotes tolerance

• Anti-VISTA mAb targeting in murine acute GVHD leads to profound deletion of allospecific CD4 T cells.

• Donor T-cell deletion occurs via FcR-dependent phagocytosis and is incompatible with peri–bone marrow transplantation calcineurin inhibitor prophylaxis.

The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be limited by graft-versus-host disease (GVHD). T-cell activation is a key factor in GVHD progression. Costimulatory signals can be counterbalanced by coinhibitory signals such as the checkpoint molecule VISTA (V-domain immunoglobulin-containing suppressor of T-cell activation)/programmed death-1 homolog that restrains activation and maintains donor T-cell quiescence. A single dose of anti-VISTA monoclonal antibody (mAb) prevents acute GVHD lethality in multiple models. Naïve donor T cells express moderate VISTA levels, which transiently increase in allo-HSCT recipients in association with T-cell receptor signaling, leading to heightened susceptibility to anti-VISTA mAb–mediated depletion, in contrast to donor T cells transferred to syngeneic recipients. Anti-VISTA mAb donor T-cell depletion was compatible with rapamycin but incompatible with peritransplant tacrolimus GVHD prophylaxis. Targeting VISTA exclusively on host cells or donor CD8⁺ T cells was not protective against GVHD lethality. Instead, anti-VISTA mAb–mediated deletion of alloreactive donor T cells depended on targeting a third (non-T) cell type. Further mechanistic studies indicated that donor T cells concurrently exposed to anti-VISTA mAb in vivo but not preincubated in vitro before adoptive T-cell transfer were eliminated via Fc receptor (FcR)-mediated phagocytosis. In a lymphoma challenge model, a graft-versus-lymphoma (GVL) effect was fully retained when anti-human VISTA mAb exclusively targeted donor CD4⁺ T cells, and was delayed but mostly retained when unseparated donor T cells were infused. In a xenogeneic GVHD model, anti-human VISTA mAb reduced donor T-cell expansion, VISTA T-cell expression levels, and recipient lethality. Together, these data support a novel clinical translational pathway in which acute GVHD lethality can be mitigated without negating the GVL effect.