Ecto-enzyme CD38: Regulator of dendritic cell migration

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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.