Ecto-enzyme CD38: Regulator of dendritic cell migration

说明(申请人提供)：免疫反应依赖于白细胞从抗原沉积部位到次级淋巴器官和感染或炎症部位的协调运动。趋化因子通过引导白细胞在体内的运输，在这一过程中发挥关键作用。尽管众所周知，白细胞表达趋化因子受体，并且可以根据趋化因子的梯度进行定向迁移，但控制趋化因子受体反应的分子机制(S)在很大程度上仍不清楚。CD38是一种ADP-核糖环化酶，催化产生钙动员的代谢物环状ADP-核糖(CADPR)，是趋化因子受体信号转导和白细胞转运的关键调节因子。我们观察到CD38缺陷小鼠的中性粒细胞迁移受损，导致炎症反应减弱和减少。我们还发现，CD38产生的cADPPR调节中性粒细胞的钙动员，中性粒细胞已被炎性趋化剂激活，如来自细菌和病毒的多肽。此外，我们还发现cADPR特异性拮抗剂可以阻断中性粒细胞对这些多肽的迁移反应。这些数据表明，CD38的小分子抑制剂可能被用来阻断中性粒细胞依赖的炎症反应。最近，我们观察到CD38缺陷小鼠的树突状细胞的迁移反应也受到了损害。具体地说，我们发现CD38缺陷的树突状细胞不能对ELC或SLC做出反应，这是一种趋化因子，引导树突状细胞从损伤或损伤部位迁移到淋巴组织。在CD38缺陷的树突状细胞中观察到的这种化学趋化反应受损导致T细胞启动无效，并显著降低T细胞依赖的免疫反应。基于我们之前的数据，我们现在假设CD38通过产生cADPR，通过调节树突状细胞的迁移来调节细胞依赖的免疫反应。为了验证这一假说，我们提出了以下具体目标：(1)我们将确定CD38是否调控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是否调控树突状细胞向炎性趋化物质的迁移，以及(3)我们将确定CD38产生的cADPR是否控制体内树突状细胞的迁移。这些实验将验证CD38拮抗剂是否有潜力被用作免疫抑制剂，通过调节白细胞的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.