Infections and the Stability of Transplantation Tolerance

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Overall Summary Transplantation tolerance, a state of hyporesponsiveness to donor antigens after cessation of therapy, is an attractive approach for achieving life-long graft acceptance without global immunosuppression. Tolerance is rare in the clinic, and even when attained can be lost over time, sometimes after infections. Understanding the barriers to the induction of transplant tolerance in the clinic, and the vulnerabilities to durable tolerance, is essential to achieving the goal of one transplant for life. One barrier to the induction of transplant tolerance in the clinic is T cell memory (Tmem). The intrinsic independence of Tmem from costimulation and their resistance to Tregs can explain the difficulty in inducing tolerance. Project 2 has identified an additional hurdle by which Tmem can antagonize the induction of transplant tolerance: a small number of Tmem can “infect” naïve T cells into acquiring memory-like features and resisting costimulation blockade (CoB) via a process of ‘linked-sensitization’. Once established, transplantation tolerance may exhibit vulnerabilities to its maintenance especially during settings of proinflammatory infection. Project 1 has identified heterogeneity in states of dysfunction achieved by polyclonal alloreactive T cells following CoB, with T cells specific for alloantigens that are rapidly downregulated in the graft following transplantation, and T cells with low affinity/avidity to graft antigens, retaining function despite CoB. These functional T cells do not pose a threat to the graft at steady state because they are controlled by Tregs. However, inflammatory cytokines elicited by some infections are known to destabilize Tregs, activate APCs and upregulate graft MHC, such that these T cells that retain function may mediate graft rejection. Both projects have identified a solution to these barriers/vulnerabilities. Project 2 found that exposing donor- reactive Tmem to a semi-allogeneic pregnancy re-programs Tmem into becoming susceptible to CoB. Project 1 shows that repeated injections of donor splenocytes can induce dysfunction in a wider repertoire of alloreactive T cells, including Tmem. The molecular mechanisms underlying the acquisition of dysfunction will be investigated and compared between projects, thus underscoring the synergy of the projects. The global hypothesis of the current submission is that understanding the mechanisms by which linked sensitization and heterogeneity in alloreactive T cell dysfunction prevent tolerance induction or break established tolerance, as well as the mechanisms by which exposure to pregnancy or to repeated donor splenocyte injections overcome these barriers, will help identify critical molecular drivers of tolerance, markers of robust versus unstable tolerance, and aid in the design of new therapeutic approaches to induce durable transplantation tolerance. Project 1 addresses the mechanisms by which the duration of alloantigen expression determines the level of T cell dysfunction post- CoB (Aim 1) and tests the hypothesis that low affinity/avidity alloreactive T cells are poised to mediate rejection during infections (Aim 2). Project 2 investigates the mechanism behind linked sensitization (Aim 1), and how CD8+ (Aim 2) and CD4+ (Aim 3) alloreactive Tmem are re-programmed by pregnancy.