PD-1 Mediated Regulation of Salivary Gland Integrity

摘要 免疫检查点在抑制免疫反应、维持自身健康等方面发挥着重要作用。 容忍和防止过度的附带损害。免疫检查点封锁使癌症发生革命性变化 免疫治疗但会导致免疫相关不良事件(IrAEs)。接受程序化细胞移植的患者 死亡蛋白1(PD-1)的阻断可发展为包括白癜风、结肠炎、内分泌疾病和干燥症在内的IRAE 综合征，一种自身免疫性疾病，其特征是免疫细胞在唾液中聚集和 泪腺，导致恶化和功能障碍。免疫细胞激活后，PD-1上调，并 在与其配体PD-L1相互作用时，PD-1信号导致增殖减少，细胞因子产生减少，并 细胞毒性。PD-1表达于涎腺浸润性淋巴细胞，包括自然杀伤细胞(NK)和 T细胞。唾液腺中的低反应性免疫细胞被认为保持了这种微妙的完整性 组织，同时无意中导致病毒潜伏期。同时试图理解为什么这个器官中的淋巴细胞 都是低反应的，我意外地发现PD-1的基因缺失会导致CD8+T细胞数量增加和 在幼稚动物的唾液腺中出现频率。更多的初步数据表明，NK细胞可能控制了 唾液腺中CD8+T细胞的增殖。基于这些数据，我假设为了保存 由于唾液腺的完整性，NK细胞可能通过PD-1/PD-L1轴控制该器官中T细胞的增殖。 因此，在特定的目标1中，我将阐明PD-1调节CD8+T细胞的分子机制。 唾液腺，并鉴定扩增的CD8+T细胞的转录组和效应功能 人口。在特定的目标2中，我将描述CD8+T细胞潜在的免疫病理后果 通过评估组织病理学和唾液分泌物在PD-1KO唾液腺中的扩张。这些研究是关于 PD-1在唾液腺免疫细胞上的表达可为IRAEs的预防和治疗提供参考。在……里面 为准备拟议的工作，我的培训一直在优秀的免疫学实验室进行。 Laurent Brossay，以及支持性病理生物学研究生计划。我的训练经验将会 通过出席和在国内和国际会议上发表演讲来丰富自己，并通过 我的赞助人。完成这项计划将使我具备一整套技能和关键的基础技能 作为一名独立研究人员取得成功所需的知识。

Abstract Immune checkpoints play an important role in restraining the immune response, maintaining self- tolerance and preventing excessive collateral damage. Immune checkpoint blockade has revolutionized cancer immunotherapy but can lead to immune related adverse events (IrAEs). Patients receiving programmed cell death protein 1 (PD-1) blockade can develop IrAEs including vitiligo, colitis, endocrinopathies, and Sicca Syndrome, an autoimmune disease characterized by the accumulation of immune cells in the salivary and lacrimal glands, leading to deterioration and dysfunction. After immune cell activation, PD-1 is upregulated, and upon interacting with its ligand PD-L1, PD-1 signaling results in reduced proliferation, cytokine production, and cytotoxicity. PD-1 is expressed on infiltrating lymphocytes of the salivary gland including natural killer (NK) and T cells. Hyporesponsive immune cells in the salivary gland are thought to retain the integrity of this delicate tissue, while inadvertently contributing to viral latency. While trying to understand why lymphocytes in this organ are hyporesponsive, I unexpectedly found that genetic loss of PD-1 results in increased CD8+ T cell number and frequency in the salivary glands of naïve animals. Additional preliminary data suggests that NK cells may control CD8+ T cell expansion in the salivary gland. Based on these data, I hypothesize that in order to preserve the integrity of the salivary gland, NK cells may control T cell proliferation via the PD-1/PD-L1 axis in this organ. Therefore, in Specific Aim 1, I will elucidate the molecular mechanism by which PD-1 regulates CD8+ T cells in the salivary gland, and characterize the transcriptome and effector functions of the expanded CD8+ T cell population. In Specific Aim 2, I will characterize the potential immunopathological consequences of CD8+ T cell expansion in the PD-1 KO salivary gland by assessing histopathology and saliva secretions. These studies of PD-1 on salivary gland immune cells should provide insights for prevention and treatments of IrAEs. In preparation for the proposed work, my training has taken place in the outstanding immunology laboratory of Dr. Laurent Brossay, as well as within the supportive Pathobiology Graduate Program. My training experience will be enriched by attending and presenting at national and international conferences, and thoughtful mentoring by my sponsor. Completion of this proposal will prepare me with a repertoire of skills and the key foundational knowledge required for a successful career as an independent researcher.