Transient depletion of donor CD4+ T cells early after HCT allows recipient tissue PD-L1 to tolerize infiltrating CD8+ T cells and to prevent acute GVHD while preserving GVL effect

Abstract

Abstract Prevention of graft-versus-host-disease (GVHD) while preserving graft-versus-leukemia/lymphoma (GVL) effect remains the Holy Grail for allogeneic hematopoietic cell transplantation (HCT). Purified donor CD4+ T cells induce strong but CD8+ T cells induce little acute GVHD (aGVHD); however, the mechanisms remain unknown. Recipient tissue expression of PD-L1 (B7H1) down-regulates aGVHD via simultaneous PD-L1 interactions with CD80 and PD-1 on donor T cells, but whether this mechanism impacts on GVL effect remains unclear. In the current studies, with MHC-mismatched HCT model of C57BL/6 donor to BALB/c recipient, we observed that 1) although sorted wild-type (WT) CD8+T cells induced no signs of aGVHD, purified PD-1−/− CD8+ T cells induced lethal aGVHD; 2) while WTCD8+ T or very low-dose (0.1×106) CD4+ T cells alone induced little signs of aGVHD, co-transplantation of them induced lethal aGVHD; 3) depletion of CD4+ T cells by anti-CD4 mAb early after HCT prevented aGVHD in wild-type but not in PD-L1−/− recipients, and the GVHD prevention is associated with increase of serum IFN-γ, upregulation of host tissue PD-L1, upregulation of CD80 and PD-1 by CD8+ T cells, as well as increase of apoptosis and anergy of tissue infiltrating CD8+ T cells; 4) interestingly, the depletion of donor CD4+ T cells augmented donor CD8+T cell proliferation without increasing anergy or apoptosis in the lymphoid tissue and preserved strong GVL effect. These results indicate that depletion of donor CD4+ T cells early after HCT leads to increasing susceptibility of donor CD8+ T cells to host tissue PD-L1-mediated apoptosis and anergy in GVHD target tissues but not in the lymphoid tissues, such that GVHD is prevented and GVL effect is preserved.