Lysophosphatidic Acid Regulation of CD8 T cell activation and function

项目摘要 细胞毒性CD 8 T淋巴细胞凭借其识别免疫球蛋白的能力在获得性免疫中发挥关键作用。 并消除病原体感染的细胞和新生肿瘤。为了实现这一重要功能，T细胞 由CD 8 T细胞表达的抗原受体（TCR）必须识别病原体来源的肽， 主要组织相容性复合体（MHC）I类受体（pMHC）。为了应对病原体感染， CD 8 T细胞的TCR-pMHC识别事件在决定随后的适应性反应如何发生中至关重要。 舱单因此，初始CD 8 T细胞的TCR信号传导不仅在启动保护性应答中很重要， 但效应CD 8 T细胞的TCR信号传导也是其有效消除CD 8 T细胞的细胞毒活性的基础。 被感染的细胞因此，适当的TCR信号传导是活化、稳健增殖和增殖的核心。 效应和记忆CD 8 T细胞的功能，最终导致病原体特异性CD 8 T细胞的运输 细胞到达感染部位并通过CD 8 T细胞溶细胞活性消除感染的细胞。 我们实验室的工作表明，内源性细胞外溶血磷脂，溶血磷脂 酸（LPA），通过由成熟的人和小鼠T细胞表达的LPAR 5 G蛋白偶联受体发出信号 并且负调节TCR信号传导、增殖和细胞毒活性。值得注意的是，这种脂质和分泌的 负责其合成的酶通常在炎症环境中升高，包括许多慢性炎症， 病原体感染然而，LPA如何在这些病理生理水平上或在这些水平上调节CD 8 T细胞生物学， 内稳态内源性水平仅被粗略地检查并且没有被很好地理解。实验 本提案中所描述的目的是提供对分子生物学的全面理解， LPAR 5信号传导负面影响TCR信号传导和体内CD 8 T细胞免疫的机制。 此外，考虑到LPA水平在慢性感染中通常会增加，我们还建议确定 建立慢性感染的病原体破坏LPA的产生以抑制T细胞免疫， 小分子抑制剂能够拮抗LPAR 5信号传导以促进增强的免疫力。 因此，这些研究的成功完成，预计不仅将扩大我们目前的 了解CD 8 T细胞如何调节以提供针对病原体感染的保护性免疫， 还可能揭示新的治疗干预途径，可以增强对持续感染的免疫力， 全球健康问题。

PROJECT SUMMARY Cytotoxic CD8 T lymphocytes fill a crucial role in adaptive immunity by virtue of their ability to recognize and eliminate pathogen-infected cells and nascent tumors. To accomplish this important function, the T cell antigen receptor (TCR) expressed by CD8 T cells must recognize a pathogen-derived peptide in the context of the major histocompatibility complex (MHC) class I receptor (pMHC). In response to a pathogen infection this TCR-pMHC recognition event by CD8 T cells is crucial in dictating how the ensuing adaptive response manifests. Thus, TCR signaling by naïve CD8 T cells is not only important in initiating a protective response but TCR signaling by effector CD8 T cells also underlies its cytotoxic activity for the efficient elimination of infected cells. Accordingly, appropriate TCR-signaling is central for the activation, robust proliferation and function of effector and memory CD8 T cells that ultimately leads to the trafficking of pathogen-specific CD8 T cells to sites of infection and elimination of infected cells via CD8 T cell cytolytic activity. Work from our lab has revealed that an endogenous extracellular lysophospholipid, lysophosphatidic acid (LPA), signals via the LPAR5 G-protein coupled receptor expressed by mature human and mouse T cells and negatively regulates TCR signaling, proliferation and cytotoxic activity. Notably, this lipid and the secreted enzyme responsible for its synthesis are often elevated in inflammatory settings including a number of chronic pathogen infections. Yet, how LPA regulates CD8 T cell biology at these pathophysiological levels or at homeostatic endogenous levels has only been cursorily examined and is not well understood. The experiments described in this proposal are designed to provide a comprehensive understanding of the molecular mechanisms by which the LPAR5 signaling negatively impacts TCR signaling and in vivo CD8 T cell immunity. In addition, given that LPA levels are often increased in chronic infections, we also propose to determine if pathogens that establish chronic infections subvert LPA production to suppress T cell immunity and whether small molecule inhibitors are able to antagonize LPAR5 signaling to promote enhanced immunity. The successful completion of these studies is thus expected to not only extend our current understanding of how CD8 T cells are regulated to provide protective immunity against pathogen infections but also may reveal new avenues of therapeutic intervention that may enhance immunity to persistent infections of global health concern.