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 be