Abstract
Development of T-cell hyporesponsiveness to donor antigen may explain the substantial decreased risk for acute rejection in the years following kidney transplantation. The underlying mechanisms of donor-specific hyporesponsiveness (DSH) are largely unknown but may allow for lowering of immunosuppressive medication. Due to the onset of DSH being more rapid and pronounced in older recipients (+55 years), we hypothesized that immunosenescence/exhaustion of T lymphocytes would be a contributing factor. This study tested whether donor-reactive recipient T cells become hyporesponsive due to exhaustion from continuous stimulation by donor antigen. Circulating donor-reactive T cells of both young and elderly stable kidney transplant recipients (N=17) before and 3-5 years after transplantation were analyzed at the single cell level for expression of exhaustion markers by multi-parameter flow cytometry followed by unsupervised and unbiased clustering. Clusters containing cells of a particular expression profile with significant differential abundance after transplantation were identified and further analyzed. Unexpectedly, our results do not demonstrate an increase in exhausted donor antigen-reactive T cells post transplantation. Instead, we demonstrate a significant decrease in donor antigen-reactive CD4+ T cells expressing T cell immunoglobulin and ITIM domain (TIGIT) long after transplantation. Further analysis at earlier timepoints indicated that this decrease is already present at six months post transplantation. Characterization of these CD4+ T donor-reactive cells expressing TIGIT revealed them to have a predominantly central and effector memory T cell phenotype and a highly poly-functional cytokine expression profile. This study has therefore identified TIGIT as a marker for a previously undescribed polyfunctional donor-reactive CD4+ T cell population whose decline following kidney transplantation may explain development of DSH.
Highlights
While the majority of acute T cell mediated rejections occur within the first 3-6 months after transplantation, the incidence declines to virtually zero by 3-5 years post kidney transplantation (KT) [1]
The 7 relevant topDA clusters all showed a decrease in abundance post KT with a median log fold change of -1.55 ranging from -1.81 to -1.29 (Figure 1B)
Similar analyses were repeated on CD3+ T cells from the same KT recipients stimulated with antigen containing an equal number but different HLA-mismatches than those observed for the donor kidney
Summary
While the majority of acute T cell mediated rejections occur within the first 3-6 months after transplantation, the incidence declines to virtually zero by 3-5 years post kidney transplantation (KT) [1]. This decreased risk is thought to arise from a gradual decrease in alloreactivity of T-cells to donor antigen while response to alloantigen of a third party is retained. A similar mechanism may be playing a role in transplant recipients with continuous stimulation by donor antigen leading to non-functional T cells with an exhausted phenotype. Exhausted T cells will lose the ability to proliferate or produce interleukin (IL)-2 followed by a decreased ability to secrete effector molecules, including inflammatory cytokines and granzymes [11]
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