*Purpose: Donor-specific allo-reactive memory CD8 T cells play a pivotal role in allo-immunity and represent a major hurdle against tolerance induction in solid organ transplantation. Hence, there is a critical need to understand the mechanisms regulating their development, function and maintenance.

*Methods: Since epigenetic modifications play a major role in a wide range of biological processes and diseases, we sought to understand these mechanisms through the lens of epigenetics.

*Results: Here, we report epigenetic and functional changes in alloreactive memory CD8 cells isolated from stable vs acutely-rejecting liver transplant patients each receiving standard of care immunosuppressive therapy. We observed low frequencies of dividing naïve and memory CD8 T cell subsets in stable liver transplant patients compared to rejecting counterparts in mixed leukocyte reactions (CTV-MLRs). Surprisingly, the majority of the allo-reactive memory CD8 T cells were found in the central memory subset (TCM) sorted from rejecting patients. Using gold-standard methods for DNA methylation analysis, we observed hyper-methylation of effector-associated (IFNγ and CD69), costimulatory molecules (CD28 and CD70), and coinhibitory molecule CTLA-4 in TCM alloreactive CD8 T cells sorted from stable liver transplant patients compared to the rejecting group.

*Conclusions: These novel data demonstrate that effector-associated epigenetic programs are acquired during allo-antigen-induced proliferation of memory CD8 T cells in stable liver transplant patients, which could be targeted for potential epigenetic-based therapies in solid organ transplantation.

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