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