*Purpose: While advances have been made in therapies that achieve tolerance in mouse transplant models, successful tolerance is still vulnerable to inflammatory challenges that can trigger graft rejection, including infections. Understanding the mechanisms by which grafts are rejected after the establishment of donor-specific tolerance may identify strategies for improving the robustness of tolerance. Transplantation tolerance is associated with exhaustion of alloreactive T cells. We hypothesized that, following induction of tolerance, there might be heterogeneity in the level of dysfunction of alloreactive T cells with distinct specificities, depending on the duration of cognate alloantigen persistence.

*Methods: To address our hypothesis, we adoptively transferred congenically labeled, tracer T cells specific for either MHC Class I antigen or MHC Class II antigen to heart graft recipients prior to inducing tolerance with anti-CD154 and an injection of donor splenocytes.

*Results: We found that, unlike donor MHC Class I-reactive T cells which persistently see antigen and become exhausted, T cells specific for donor MHC Class II, an alloantigen transiently expressed post-transplantation, retained some functionality during tolerance. Prolonging the exposure of these T cells to their cognate antigen aggravated their dysfunction and improved transplant outcome, rendering grafts more resistant to Listeria-monocytogenes dependent rejection.

*Conclusions: These findings demonstrate that treatments designed to induce dysfunction in a broader array of alloreactive T cells, by prolonging exposure to more alloantigens, improve the robustness of tolerance.

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