Bootcongres

Background Memory T cells generated in response to a pathogen can also recognize alloantigens, so called heterologous immunity. The best known example is the public cross-reactivity of Epstein-Barr virus (EBV) B8 FLR-specific T cells to HLA B*44:02 expressing allogeneic cells. In healthy individuals, virus-specific T cells frequently cross-react to alloantigens, yet little is know about the impact of heterologous immunity on alloimmune responses in kidney transplant recipients. Therefore, we here studied to what extent circulating virus-specific T cells recognize alloantigens of donor-origin. Methods Peripheral blood mononuclear cells of kidney transplant recipients who experienced a cytomegalovirus (CMV) and/or EBV infection (n=6 primary infections, n=15 reactivations) were collected longitudinally. The cells were labelled with CFSE and cultured with irradiated donor cells in a mixed-lymphocyte-reaction. At day 6, cells were stained with viral peptide MHC tetramers and analyzed by flow cytometry. Virus and alloantigen cross-reactive T cells were identified as virus-specific T-cells that proliferate in response to alloantigen (tetramer+CFSEdim). Results In 11 out of 21 patients, we found cross-reactivity to donor-antigen for at least one viral epitope. Cross-reactive T cells were present prior to transplantation (n=3) or appeared during or after viral infection (n=8). Cross-reactivity was never observed prior to occurrence of a primary infection, implicating that cross-reactive T cells are generated in response to the virus and not in response to the allogeneic kidney transplant. Cross-reactivity to donor-antigen was in all cases only transiently observed, while cross-reactivity to fully mismatched 3rd party cells was observed at multiple time points after transplantation. Moreover, the number of EBV B8 FLR-specific T cells rapidly decreased after transplantation in HLA B8 positive recipients who received a kidney of a HLA B44 positive donor. The temporary presence of donor-antigen cross-reactive T cells in the circulation, suggests they might home to the kidney transplant and/or are actively down-regulated due to tolerance induction towards the graft. Conclusion Our results demonstrate that cross-reactivity of virus-specific T cells to donor-antigens is commonly observed in kidney transplant recipients.