Confronting the Barrier to Stable Transplantation Tolerance Posed by Memory T Cells

项目2摘要 移植耐受有望促进长期同种异体移植物接受，同时避免需要 终身免疫抑制及其相关问题。在过去的十年中， 已经通过造血干细胞移植或常规免疫疗法的戒断来实现耐受性。 免疫抑制然而，绝大多数移植受者不能实现同种异体移植耐受， 一部分手术耐受移植受者最终经历移植物丢失。高频率的 记忆同种异体反应性CD 4+或CD 8 + T细胞已被鉴定为成功诱导免疫应答的有效屏障。 移植耐受仍然迫切需要确定新的战略，以克服 记忆T细胞构成的屏障;项目2提出解决这一需求。我们最近发现记忆T 细胞抵抗感染耐受机制，不能获得细胞内在的功能低下状态， 幼稚的T细胞此外，在携带记忆T细胞的致敏受体中， 抗原，我们报告说，较大的幼稚供体特异性CD 4 + Tconv库也会对 共刺激阻断诱导的耐受性。我们将这种现象称为“关联致敏”，并指出， 了解共刺激阻断诱导的同种异体移植耐受的这种屏障的机制， 不仅与具有异源记忆T细胞的受体相关，而且还可以导致识别新的 与共刺激阻断协同作用以实现移植耐受的靶点。目标1将侧重于 确定了连锁致敏的机制。我们观察到记忆T细胞对 编程到细胞内在功能减退状态识别知识的差距，是否，以及如何，记忆 T细胞可以被编程为耐受性。为此，我们利用生理上强大的过程， 妊娠，其编程对半同种异体胎儿特异性的T细胞，以自发地接受随后的 后代匹配的心脏移植值得注意的是，我们发现怀孕能够对记忆T细胞进行编程， 产生的排斥反应完全不匹配的皮肤移植，成为功能减退，容易受到共同的， 刺激阻断诱导移植耐受。我们将定义怀孕计划的机制， 分别在目的2和3中，CD 8+和CD 4 + T细胞的功能减退。拟议的研究与 产后移植受者，并可能产生一个概念和潜在的治疗路线图， 编程功能减退和对共刺激阻断诱导的记忆移植耐受的易感性 T细胞。因此，从我们的研究中获得的见解最终将适用于致敏的移植受者， 男女都有。

Project 2 Summary Transplantation tolerance promises to facilitate long-term allograft acceptance while avoiding the need for life-long immunosuppression and its associated problems. In the past decade, operational clinical transplantation tolerance has been achievable through hematopoietic stem cell transplantation or weaning of conventional immunosuppression. However, the vast majority of transplant recipients fail to achieve allograft tolerance, and a subset of operationally tolerant transplant recipients eventually experience graft loss. High frequencies of memory alloreactive CD4+ or CD8+ T cells have been identified as potent barriers to the successful induction of transplantation tolerance. There continues to be an urgent need to identify new strategies for overcoming the barrier posed by memory T cells; Project 2 proposes to address this need. We recently showed that memory T cells resist infectious tolerance mechanisms, and cannot acquire the cell-intrinsic hypofunctional states attained by naïve T cells. Moreover, in sensitized recipients harboring memory T cells directed to just a single donor antigen, we reported that the larger repertoire of naïve donor-specific CD4+ Tconv also develops resistance to co-stimulation blockade-induced tolerance. We refer to this phenomenon as “linked sensitization” and posit that understanding the mechanism underlying this barrier to co-stimulation blockade-induced allograft tolerance is not only relevant to recipients with heterologous memory T cells, but also can lead to the identification of new targets that synergize with co-stimulation blockade to achieve transplantation tolerance. Aim 1 will focus on defining the mechanism of linked sensitization. Our observations that memory T cells are resistant to being programmed into cell-intrinsic hypofunctional states identify a gap in knowledge as to whether, and how, memory T cells may be programmed to tolerance. To this end, we leveraged the physiologically powerful processes of pregnancy that program T cells specific for the semi-allogeneic fetus to spontaneously accept subsequent offspring-matched heart allografts. Remarkably, we show that pregnancy is able to program memory T cells, generated by the rejection of fully mismatched skin grafts, to become hypofunctional and susceptible to co- stimulation blockade-induced transplant tolerance. We will define the mechanisms by which pregnancy programs hypofunction in CD8+ and CD4+ T cells in Aims 2 and 3, respectively. The proposed studies have direct relevance to post-partum transplant recipients, and will likely yield a conceptual and potentially therapeutic roadmap for programming hypofunction and susceptibility to co-stimulation blockade-induced transplant tolerance in memory T cells. Thus, insights gained from our studies will ultimately be applicable to sensitized transplant recipients of both sexes.