PD-1 Mediated Regulation of Salivary Gland Integrity

摘要 免疫检查点在抑制免疫应答、维持自身免疫功能、 容忍和防止过度的附带损害。免疫检查点阻断彻底改变了癌症 免疫治疗，但可能导致免疫相关的不良事件（IrAE）。接受编程细胞治疗的患者 死亡蛋白1（PD-1）阻断可导致IrAE，包括白癜风、结肠炎、内分泌病和干燥症 综合征，一种自身免疫性疾病，其特征是免疫细胞在唾液中的积累， 泪腺，导致恶化和功能障碍。免疫细胞活化后，PD-1上调， 在与其配体PD-L1相互作用后，PD-1信号传导导致增殖、细胞因子产生和细胞凋亡减少。 细胞毒PD-1在唾液腺的浸润淋巴细胞上表达，包括自然杀伤细胞（NK）和 T细胞。唾液腺中的低反应免疫细胞被认为保留了这一微妙的完整性。 组织，而无意中有助于病毒潜伏期。在试图理解为什么这个器官中的淋巴细胞 我意外地发现，PD-1的遗传缺失导致CD 8 + T细胞数量增加， 在幼稚动物的唾液腺中的频率。额外的初步数据表明，NK细胞可能控制 唾液腺中的CD 8 + T细胞扩增。根据这些数据，我假设，为了保护 在唾液腺的完整性方面，NK细胞可以通过该器官中的PD-1/PD-L1轴控制T细胞增殖。 因此，在具体目标1中，我将阐明PD-1调节CD 8 + T细胞的分子机制， 唾液腺，并表征扩增的CD 8 + T细胞的转录组和效应子功能 人口在具体目标2中，我将描述CD 8 + T细胞的潜在免疫病理学后果， 通过评估组织病理学和唾液分泌物来观察PD-1 KO唾液腺中的扩增。这些研究 PD-1对唾液腺免疫细胞的作用为IrAE的预防和治疗提供了新的思路。在 为准备拟议的工作，我的培训已经发生在杰出的免疫学实验室博士。 Laurent Brossay，以及支持病理生物学研究生课程。我的培训经验将 通过参加国家和国际会议并在会议上发言，以及通过以下方式进行周到的指导， 我的担保人完成本计划书后，我将掌握一整套技能， 作为一名独立研究人员，成功的职业生涯所需的知识。

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.