Role of SLAMF immunoregulatory molecules in MS disease processes

Abstract

Abstract In our proteomic analysis of cerebrospinal fluid (CSF) we found signaling lymphocyte activation molecules family (SLAMF) upregulated in multiple sclerosis (MS) patients in comparison to controls. The goal of this project is to explore the role of SLAMF molecules in MS. To identify immune cells that express and secrete SLAMF molecules in the intrathecal (CSF) environment, we performed immunophenotyping of matched blood and CSF leukocytes and dynamic in-vitro experiments, co-culturing leukocytes with EBV and CMV viral lysates. This antigen-specific activation of a sizeable proportion of T and B cells allowed the investigating of changes in surface expression and secretion of SLAMF molecules. SLAMF2 was broadly expressed, however CSF CD8+ T cells and monocytes had higher SLAMF2 expression in comparison to blood. Stimulation down-modulated SLAMF2 on T cells, but upregulated it on B cells. SLAMF3 was expressed on cells of adaptive, but not innate immunity and CD4+ T cells expressed higher levels of SLAMF3 in CSF than in blood. Upon activation, SLAMF3 expression did not change and the soluble form did not accumulate in supernatants. SLAMF5 was broadly expressed, with particularly higher levels on cells of innate immunity (monocytes and dendritic cells). CSF T and B cells had lower SLAMF5 levels than blood T&B cells. SLAMF6 was strongly expressed on T, B and NK cells; its expression levels did not vary between compartments or upon activation. Finally, SLAMF7 was expressed on cytotoxic T cells, NK cells and plasma cells, with significant upregulation on all antigen-presenting cells upon activation. We explored its role in cytotoxicity, but found no effect of SLAMF7 blockade or sSLAMF7 addition on NK-mediated killing of MHC-I-deficient targets.