Ecto-enzyme CD38: Regulator of dendritic cell migration

描述（由申请人提供）：免疫应答依赖于白细胞从抗原沉积部位、到次级淋巴器官、到感染或炎症部位的协调运动。趋化因子在这一过程中发挥关键作用，通过指导白细胞在全身的运输。虽然众所周知，白细胞表达趋化因子受体，并可根据趋化因子梯度定向迁移，但控制趋化因子受体反应的分子机制仍在很大程度上是未知的。CD38是一种adp核糖基环化酶，它催化钙动员代谢物环adp核糖（cADPR）的产生，似乎是趋化因子受体信号传导和白细胞运输的关键调节因子。我们观察到，中性粒细胞迁移在cd38缺陷小鼠中受损，导致炎症反应减弱和减少。我们还发现，由cd38产生的cADPPR调节被炎症化学引诱剂（如来自细菌和病毒的肽）激活的中性粒细胞中的钙动员。此外，我们发现cadpr特异性拮抗剂阻断中性粒细胞对这些肽的迁移反应。这些数据表明cd38的小分子抑制剂可能潜在地用于阻断嗜中性粒细胞依赖性炎症反应。最近，我们观察到树突状细胞的迁移反应在CD38缺陷小鼠中也受到损害。具体来说，我们发现缺乏cd38的树突状细胞不能响应ELC或SLC（指导树突状细胞从损伤部位迁移到淋巴组织的趋化因子）而迁移。这种受损的趋化反应观察到缺乏incd38的树突状细胞导致T细胞启动效率低下和T细胞依赖性免疫反应显着降低。基于我们之前的数据，我们现在假设CD38通过其产生cADPR，通过调节树突状细胞的迁移来调节细胞依赖性免疫反应。为了验证这一假设，我们提出了以下具体目标：(1)我们将确定CD38是否调节所有成熟树突状细胞亚群向ELC或SLC的迁移；(2)我们将确定CD38是否调节树突状细胞向炎症化学引诱剂的迁移；(3)我们将确定CD38产生的cADPR是否控制体内树突状细胞的运输。这些实验将验证CD38拮抗剂是否有潜力被用作免疫抑制剂，通过调节白细胞运输来减弱免疫反应。

DESCRIPTION (provided by applicant): Immune responses are dependent on the coordinated movement of leukocytes from sites of antigen deposition, to secondary lymphoid organs and to sites of infection or inflammation. Chemokines play a critical role in this process by directing leukocyte trafficking throughout the body. Although it is well known that leukocytes express chemokine receptors and can migrate directionally in response to chemokine gradients, the molecular mechanism(s) that control chemokine receptor responses are still largely unknown. CD38, an ADP-ribosyl cyclase, that catalyzes the production of the calcium-mobilizing metabolite cyclic ADP-ribose (cADPR), appears to be a critical regulator of chemokine receptor signaling and leukocyte trafficking. We observed that neutrophil migration is impaired in CD38-deficientmice resulting in attenuated and reduced inflammatory responses. We also found that the cADPPR produced byCD38 modulates calcium mobilization in neutrophils that have been activated with inflammatory chemoattractants such as peptides derived from bacteria and viruses. Furthermore, we showed that cADPR-specific antagonists block the migratory response of neutrophils to these peptides. The data suggest that small molecule inhibitors of CD38could potentially be used to block neutrophil-dependent inflammatory responses. Recently, we observed that the migratory response of dendritic cells is also impaired in CD38 deficient mice. Specifically, we found that CD38-deficient dendritic cells cannot migrate in response to ELC or SLC, chemokines that direct dendritic cells to migrate from sites of damage or injury to lymphoid tissues. This impaired chemotactic response observed inCD38-deficient dendritic cells results in inefficient T cell priming and significantly reduced T cell-dependent immune responses. Based on our previous data, we now hypothesize that CD38, through its production of cADPR, regulates cell-dependent immune responses by modulating the migration of dendritic cells. To test this hypothesis we have proposed the following Specific Aims: (1) we will determine whether CD38 regulates migration of all mature dendritic cell subsets to ELC or SLC, (2) we will determine whether CD38 regulates the migration of dendritic cells to inflammatory chemoattractants and (3) we will determine whether cADPR production by CD38 controls dendritic cell trafficking in vivo. These experiments will validate whether CD38 antagonists have the potential to be used as immunosuppressive agents that attenuate immune responses by modulating leukocyte trafficking.