Resilience of T cell-intrinsic dysfunction in transplantation tolerance

Abstract

Following antigen stimulation, naïve T cells differentiate into memory cells that mediate antigen clearance more efficiently upon repeat encounter. Donor-specific tolerance can be achieved in a subset of transplant recipients, but some of these grafts are rejected after years of stability, often following infections. Whether T cell memory can develop from a tolerant state and whether these formerly tolerant patients develop antidonor memory is not known. Using a mouse model of cardiac transplantation in which donor-specific tolerance is induced with costimulation blockade (CoB) plus donor-specific transfusion (DST), we have previously shown that systemic infection with Listeria monocytogenes (Lm) months after transplantation can erode or transiently abrogate established tolerance. In this study, we tracked donor-reactive T cells to investigate whether memory can be induced when alloreactive T cells are activated in the setting of tolerance. We show alloreactive T cells persist after induction of cardiac transplantation tolerance, but fail to acquire a memory phenotype despite becoming antigen experienced. Instead, donor-reactive T cells develop T cell-intrinsic dysfunction evidenced when removed from the tolerant environment. Notably, Lm infection after tolerance did not rescue alloreactive T cell memory differentiation or functionality. CoB and antigen persistence were sufficient together but not separately to achieve alloreactive T cell dysfunction, and conventional immunosuppression could substitute for CoB. Antigen persistence was required, as early but not late surgical allograft removal precluded the acquisition of T cell dysfunction. Our results demonstrate transplant tolerance-associated T cell-intrinsic dysfunction that is resistant to memory development even after Lm-mediated disruption of tolerance.

Sparse sampling of water density fluctuations near liquid-vapor coexistence

“…Simulations were performed in NVT-ensemble with a buffering water-vapor interface, which keeps the system at its coexistence pressure. 16,51,64 To allow for equilibration, the first 500 ps were discarded from each biased simulation.…”

“…35,[47][48][49] Thus, characterizing the free energetics of water density fluctuations can shed light on the mechanistic pathways associated with wetting-dewetting transitions in such systems, and also inform the magnitude of the associated barriers. 33,36,45,[50][51][52][53][54][55] To characterize the free energetics of rare water density fluctuations, it becomes necessary to employ enhanced sampling techniques, such as umbrella sampling, which are computationally expensive. However, umbrella sampling can become prohibitively expensive when the simulations themselves are very expensive or when a large number of biased simulations are needed.…”

T cell exhaustion is associated with antigen abundance and promotes transplant acceptance

“…We found that IRF4 deletion leads to transplant tolerance by inducing an exhaustion‐like phenotype of T cells, evident by their high PD‐1 expression and impaired cytokine production 11,12 . Miller et al 13 demonstrated that CD154 blockade plus donor‐specific transfusion, an experimental approach to transplant tolerance, also induces a PD‐1 hi phenotype of alloreactive T cells. Because IRF4 deletion or CD154 blockade impairs T cell effector function, T cell state under those conditions was called “T cell dysfunction” rather than exhaustion.…”

Linked sensitization by memory CD4+ T cells prevents costimulation blockade–induced transplantation tolerance

“…Naive Tconvs subject to linked sensitization acquire a phenotype of memory Tconvs. Donor-specific CD4 + Tconvs in tolerant recipients display a distinct phenotype, including low tetramer-binding avidity, reduced proliferation, and increased expression of coinhibitory molecules programmed cell death 1 (PD-1), folate receptor 4 (FR4), and CD73 (50,57,58). We showed that Tconvs from naive and N-Tol retained low 2W:I-A b tetramer-binding avidities, whereas memory Tconvs from 2W-OVA-S-Tol recipients started with higher 2W:I-A b tetramer binding prior to HTx, which further increased post-HTx (Figure 6A).…”