Co-stimulation of allo responsive NK cells with an NK cell-specific ligand enhances allo-specific rejection and memory in prenatal chimeras 4828

Abstract Description Prenatal foreign antigen exposure leads to lifelong stable tolerance, but also can result in non-tolerance to the donor antigen and cause graft rejection. In prenatal allotransplantation model (Balb/c to C57BL/6), allo-specific (Ly49D) NK cells play a key role in engraftment or rejection. We previously reported that NK cells that are prenatally exposed to alloantigens influence allo-specific T cell responses depending on the chimerism level. Probing deeper into prenatal NK-T cell regulation, we hypothesized that activation by that NK cell-specific m157 molecule acts as a co-stimulatory signal to enhance allograft rejection. Therefore, we prenatally introduced the m157 antigen into allogeneic chimeras and analyzed engraftment, NK cell receptor expression and T cell cytotoxicity. Prenatal exposure to m157 enhanced allograft rejection and resulted in a higher initial chimerism threshold for stable engraftment. Additionally, rejecter chimeras exhibited stronger T cell responses after prenatal m157 exposure. Lastly, allospecific tolerance was associated with down-regulation/elimination of Ly49H receptor or receptor-bearing NK cells. Collectively, these results suggest that the m157 viral ligand acts as a prenatal costimulatory signal for NK cells to direct T cell allospecific responses without direct T cell recognition. These findings have implications in the current understanding of prenatal tolerance to inherited or acquired antigens. Funding Sources Supported by NIH R01HL103745 and Lurie Children’s Hospital Research Foundation to A.F.S. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)