*Purpose: After kidney transplantation, donor-specific hyporesponsiveness (DSH) develops which is defined as a lowered response of alloreactive T cells to donor antigen while retaining response to a third party antigen. This study measures changes in phenotype and function of donor-reactive T cells after transplantation to better understand DSH development and guide lowering of immunosuppressive medication.

*Methods: This study integrates multiparameter flow cytometry-based assays to characterize phenotype and function of circulating donor-reactive (vs third party-reactive) CD4+ and CD8+ T cells over time. Paired samples were taken from stable kidney transplant recipients (N=46) before, at 3-5 years and more than 5 years after transplantation. Donor-reactive T cells were identified by CD137 expression and data on T cell differentiation status and transcription factor expression evaluated by unsupervised clustering. Proportions of polyfunctional donor-reactive CD137+ T cells capable of producing multiple pro-inflammatory cytokines were characterized as well as proliferation towards donor-antigen.

*Results: The data point to progressive and specific loss of activated donor-reactive T cells capable of producing pro-inflammatory cytokines after transplantation. The number of circulating CD4+ donor-reactive T cells declined within the first 3-5 years after transplantation and became virtually undetectable in the years thereafter. The donor-reactive CD8+ T cells declined substantially only after >10 years. The decrease in donor-reactive CD4+ T cells was primarily within the effector memory subset and within T cells capable of producing two or more pro-inflammatory cytokines (TNF-α, IFN-γ and IL-2). This reduction in polyfunctional donor-reactive CD4+ T cells was strongly correlated with the reduced proliferation of CD4+ T cells following kidney transplantation. The frequency of third party-reactive T cells did not alter after transplantation indicative of a donor-specific effect and not an aspecific effect of immunosuppressive medication.

*Conclusions: This study detected a decline in highly active donor-reactive T cells capable of producing multiple pro-inflammatory cytokines from the circulation in a time-after transplantation dependent fashion. The loss of polyfunctional donor-reactive effector memory CD4+ T cells likely plays an important role in the development of DSH in kidney transplant recipients.

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