Novel roles of semaphorin-3E in the regulation of phenotypes and functions of natural killer cells and dendritic cells

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Alamri, Abdulaziz
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Natural killer (NK) cell is an important innate immune cell that mediates direct antiviral and antitumor immunity. Dendritic cells (DCs) are antigen-presenting cells that undergo maturation/activation programs to link innate and adaptive immunity, and to regulate specific adaptive T cell responses. Semaphorin-3E (Sema-3E) is a member of the semaphorin family of proteins that play diverse regulatory functions in various immune responses in vitro and in vivo upon binding to the receptor PlexinD1. Whether Sema-3E and its cognate receptor PlexinD1 were involved in the regulation of NK-cell and DC phenotypes and functions, and thereby NK/DC crosstalk remained to be investigated. First, I investigated the role of Sema-3E in regulating NK cell development and function. I observed that Sema-3E deficiency did not affect NK cell development, the major NK cell receptors, or cell migration properties. Interestingly, I observed that Sema-3E-deficient NK cells were impaired in cell-mediated cytotoxicity and cytokine release. Next, I investigated the role of Sema-3E in regulating DC phenotype and function. I found that Sema-3E-deficient mice displayed higher CD11c+ cell number in bone marrow-derived DCs (BMDCs). Moreover, immature and mature splenic DCs from Sema-3E-deficient mice display an altered MHC class II phenotype. Of interest, Sema-3E-deficient immature and LPS-matured BMDCs showed upregulated expression of IL-12/IL-23p40 whereas Sema-3E-deficient immature splenic DCs downregulated IL-12/IL-23p40 compared to wild type (WT) controls. Sema-3E binds directly to PlexinD1to mediate different effector functions. Interestingly, steady-state PlexinD1-deficient BMDCs displayed higher production levels of proinflammatory cytokines, including IFN-γ, IL-12/IL-23p40, and IL-6. PlexinD1-deficient LPS-matured splenic DCs, but not BMDCs, selectively upregulated IFN-γ and IL-12/IL-23p40. Lastly, I investigated the role of Sema-3E in regulating NK cell migration in NK/DC crosstalk. I observed that the conditioned medium of immature Sema-3E-deficient BMDCs contained higher MCP-1 and MIP-1α chemokine levels compared to WT controls. Unlike for BMDCs, the conditioned medium of Sema-3E-deficient immature and LPS-matured splenic DCs did not affect NK cell migration. Together, these findings established novel roles of Sema-3E in the regulation of NK-cell and DC functions. The latter could be important in understanding immune dys-regulation in allergic asthma and/or future development of immunotherapy for cancer and infectious diseases.
Natural killer cell, Dendritic cells, Semaphorins, Semaphorin-3E, PlexinD1, Toll-like receptors, Phenotype, Function