Endowing human CD8 T cells with a veto-like recognition capacity via the electroporation of MHC-I/CD3ζ mRNA

Graft-versus-host disease (GVHD) and transplant rejection as a result of host-versus-graft (HVG) response have remained two major complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). When donors are partially HLA-mismatched unrelated or haploidentical related, their severity correlates with the degree of HLA disparity. Specific elimination of alloreactive donor or recipient T cells targeting the mismatched HLA products could markedly alleviate both complications while only minimally affecting graft-versus-tumor (GVT) response or engraftment. To redirect human CD8 T cells against alloreactive CD8 T cells we electroporate these cells with in-vitro-transcribed mRNA encoding MHC-I heavy chains fused with the signaling portion of CD3ζ. Here we show that peripheral blood human CD8 T cells expressing H-2K^b/CD3ζ or H-2K^d/CD3ζ respond to anti-MHC-I stimuli in a strictly specific manner. This study paves the way for further advancing this approach as a means to dampen GVHD and HVG that are caused by HLA disparity in allo-HSCT.