G Protein Coupling Signaling As Regulators Of Dendritic Cell Maintenance And Function In Immune Responses

Abstract Dendritic cells (DCs) are well known as the professional antigen presenT-cells (APCs), which can scan peripheral tissues where they can recognize, uptake, process and present all kinds of antigens, including pathogens and tumor antigens, to antigen specific naïve T-cells within the lymphoid organs. In these processes, DCs form a remarkable bridge between innate and adaptive immunity by interacting with various lymphoid and myeloid cells. DCs originate from the bone marrow hematopoietic progenitor cells and DC precursors migrate from blood to tissues for developing into immature DCs. Upon activation, DCs migrate to stimulate T-cells and induce immune responses to protect our bodies. However, the mechanism for maintenance and activation of DCs on the local microenvironment is largely unknown. As GPCR signaling has important roles in many cellular process, including cell division, survival, migration and adhesion. Using competitive mixed BM chimaera, I checked some molecules involved in GPCR signal pathways, and found that geneA was required intrinsically in the maintenance of CD4+ conventional DCs (cDCs) in the spleen, as evidenced by observation that geneA-deficient CD4+ DCs were dramatically decreased in spleen but increased in blood. By in vivo 3min CD45-PE labeling assay, cells exposed to the vascular compartment in spleen can be selectively labeled. With this method, I found without geneA, CD4+ DCs had disadvantage to be maintained in the blood-exposed region within the spleens under the shear flow stress. I further showed that geneA-deficient CD4+ DCs had disadvantage to uptake blood-derived Sheep-blood cells (SRBCs). Besides this stimulation, this signal also controlled CD4+ DCs activation in response to different kinds of TLR stimulators. By OT-II adoptive transfer system, geneA-expressing DCs were required to support T-cell proliferation and differentiation efficiently. Therefore, these results demonstrate a key role of G protein-coupled receptor signaling in promoting the maintenance and activation of DCs, and reveal a mechanism in DC positioning in vivo. Thus, it will broaden our understanding of GPCR signaling in DC immunology, which is pivotal for modulating DCs for vaccines and therapies against pathogens, autoimmune diseases and tumors. Citation Format: Dan Liu, Jason G. Cyster. G protein coupling signaling as regulators of dendritic cell maintenance and function in immune responses [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B173.