Resilience of T cell-intrinsic dysfunction in transplantation tolerance
Resilience of T cell-intrinsic dysfunction in transplantation tolerance
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DOI：
10.1073/pnas.1910298116
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发表时间：
2019-11-19
影响因子：
11.1
通讯作者：
Alegre, Maria-Luisa
中科院分区：
文献类型：
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作者：
Miller, Michelle L.;McIntosh, Christine M.;Alegre, Maria-Luisa
抗原刺激后，初始T细胞分化为记忆细胞，在重复接触时更有效地介导抗原清除。供体特异性耐受可以在一部分移植受体中实现，但其中一些移植物在稳定多年后被排斥，通常是在感染后。T细胞记忆是否可以从耐受状态发展而来，以及这些先前耐受的患者是否发展出抗供体记忆尚不清楚。使用小鼠心脏移植模型，其中供体特异性耐受是通过共刺激阻断（CoB）加供体特异性输血（DST）诱导的，我们先前已经表明，移植后几个月单核细胞增生李斯特菌（Lm）的全身感染可以侵蚀或暂时消除已建立的耐受性。在这项研究中，我们追踪了供者反应性T细胞，以研究当同种异体反应性T细胞在耐受的情况下被激活时是否可以诱导记忆。我们发现同种异体反应性T细胞在诱导心脏移植耐受后持续存在，但尽管经历了抗原，但未能获得记忆表型。相反，供体反应性T细胞发展T细胞内在功能障碍，当从耐受环境中移除时证明。值得注意的是，Lm感染后的耐受性并没有拯救同种异体反应性T细胞的记忆分化或功能。CoB和抗原持久性是足够的，但不单独实现同种异体反应性T细胞功能障碍，和常规的免疫抑制可以替代CoB。抗原持久性是必需的，因为早期而非晚期的同种异体移植物手术切除排除了T细胞功能障碍的获得。我们的研究结果表明，移植耐受相关的T细胞内在功能障碍，即使在LM介导的耐受性破坏后，也能抵抗记忆的发展。
Following antigen stimulation, naive 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.