T cell alloreactivity to the kidney transplant: Lessons from the elderly

This thesis marks the first comprehensive exploration of donor reactivity in T cells in relation to recipient age in kidney transplant patients. The CD137 assay, utilizing short-term stimulation with donor antigens, facilitated identifying changes in donor-reactive T cells in peripheral blood. Using single-cell techniques at both protein (flow cytometry) and RNA levels (single-cell RNA sequencing), we characterized the phenotype and function of donor-reactive T cells before and after transplantation. Inclusion of a third-party control confirmed donor-specific effects within each study. Our findings reveal that the development of donor-specific hyporesponsiveness (DSH) in T cells of stable kidney transplant patients is primarily attributed to the specific deletion of polyfunctional donor-reactive CD4+ T cells through activation-induced cell death (AICD), coupled with a loss of proliferation upon stimulation with donor antigens. This specific cell population proves to be a risk factor, with a high pre-transplantation frequency associated with acute T cell-mediated rejection (TCMR). Notably, we demonstrate for the first time that age-related impairment of IL-2 signaling leads to reduced CD8+ T cell proliferation. Paired with a lower frequency of polyfunctional CD4+ T cells upon alloantigen stimulation, associated with aging, this could explain the reduced risk of acute rejection in older individuals. These findings underscore the crucial role of analyzing donor-reactive T cells at the individual cell level, with implications for clinical monitoring and future research. The study deepens understanding of how aging and transplantation are linked to developing donor tolerance, offering potential insights for optimizing immunosuppressive medication.