Pregnancy-induced T cell exhaustion: an opportunity to reduce immunosuppression

项目摘要(摘要) 怀孕是一种常见的同种免疫事件，会影响妇女的移植机会和结局。 虽然母体免疫系统的T细胞通常会被胎儿同种异体抗原激活，但目前尚不清楚 胎儿抗原刺激的T细胞在妊娠期间是否分化为规范的记忆细胞。这个 这些在母体中经历过抗原的T细胞的长期命运和召回潜力是 对女性移植受者特别重要，她们的T细胞可能能够迅速排斥 与先前怀孕的人共享组织抗原的捐献器官。不幸的是，我们对T细胞的了解很差 有妊娠史的妇女的命运导致了移植中显著的性别差异。 在我们的小鼠模型中的初步数据表明，怀孕期间的胎儿抗原促进分化 CD8+T细胞在母系中持续存在，但功能有限。而这些T细胞可以 它们仍然介导同种异体移植的快速排斥反应，似乎与在移植过程中分化的记忆T细胞不同 其他类型的同种异体免疫。同种异体免疫中不同人群的抗原敏感T细胞 移植受者可能对免疫抑制有独特的要求。在这项提案中，我们将 研究妊娠或移植诱导的抗原相关T细胞群是如何 彼此不同(目标1)，并确定这些差异是否会促进免疫抑制 妇女的减少战略(目标2)。我们预计，这些研究产生的知识将改变 目前的免疫抑制策略，以改善对同种免疫移植受者的护理。

PROJECT SUMMARY (ABSTRACT) Pregnancy is a common alloimmunizing event that impacts transplant access and outcomes among women. Although T cells of the maternal immune system are routinely activated by fetal alloantigen, it is unclear whether T cells stimulated by fetal antigen differentiate into canonical memory cells during pregnancy. The long-term fate and recall potential of these antigen-experienced T cells in the maternal repertoire are of particular importance to female transplant recipients, whose T cells may be capable of rapid rejection of a donor organ that shares tissue antigens with a prior pregnancy. Unfortunately, our poor understanding of T cell fate in women with a history of pregnancy has contributed to significant gender disparity in transplantation. Preliminary data in our mouse model suggest that fetal antigen during pregnancy promotes the differentiation of CD8+ T cells that persist in the maternal repertoire but have restricted functionality. While these T cells can still mediate rapid allograft rejection, they appear to be distinct from memory T cells that differentiate during other types of alloimmunization. Different populations of antigen-experienced T cells in alloimmunized transplant recipients may have unique requirements for immunosuppression. In this proposal, we will investigate how populations of antigen-experienced T cells induced by either pregnancy or transplantation differ from one another (Aim 1) and determine whether these differences promote immunosuppression reduction strategies in women (Aim 2). We anticipate that the knowledge generated by these studies will alter current immunosuppression strategies to improve the care of alloimmunized transplant recipients.