Role of Natural Killer Cell Diversity in Multiple Sclerosis Risk and Disease Course

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Project Summary The goal of this project is to comprehensively characterize the role of polymorphic natural killer (NK) cell receptors in multiple sclerosis (MS). Substantial data implicate NK cells in MS pathogenesis, but their precise function in mediating risk and disease course is poorly understood. Given that a large and diverse set of highly variable receptors govern NK cell activity, their characterization in MS promises to yield important insights into the role of NK cells in disease. Thus, we will characterize the nature and extent of the association of genomic variation of NK receptors across a set of diverse, established and deeply phenotyped MS cohorts. This goal will be achieved via our novel high-throughput, high-resolution next-generation sequencing (NGS) methodology. Using state-of-art technologies, we will contextualize this genomic variation by considering NK cell phenotype in disease. Finally, we will explore the functional implications of the observed NK receptor variation, allowing a mechanistic explanation of the impact of NK receptor expression to more fully understand the role of these highly variable receptors in MS. Together, the leukocyte receptor complex (LRC) on chromosome 19 and the natural killer complex (NKC) on chromosome 12 encode more than 90 distinct NK cell receptors, including the extremely polymorphic KIR (killer-cell immunoglobulin-like receptor) and LILR (leukocyte immunoglobulin-like receptors). In the work described here, we approach these complex systems across several key modalities, examining genomic, phenotypic and functional variation of NK receptors in MS to provide the first comprehensive depiction of the role of NK receptors in disease. Our preliminary work in a cohort of European ancestry identified a significant association of KIR variation with risk for developing MS, as well as with clinical and MRI features of disease. In Specific Aim 1, we will extend these findings to diverse patient populations and characterize KIR variation in MS across ancestries, in an additional cohort with longitudinal clinical and MRI data, and by investigating genomic variation of all known polymorphic NK receptors and their corresponding ligands. In Specific Aim 2, we will more fully resolve the role of these receptors in disease course by examining temporal expression patterns of NK cell receptors in individuals with MS through longitudinal CyTOF analysis. Finally, in Specific Aim 3, we will contextualize these results by harnessing CRISPR technology to characterize the impact of NK cell receptor expression level on NK cell function. This work promises to fill critical gaps in our understanding of the role of NK cells in MS. Because NK cell activity is tightly governed by the highly variable receptors that we investigate in this proposal, this work will provide important insight into the regulatory mechanisms underlying the influence of NK cells in MS susceptibility and disease course. The results will bear both on our understanding of disease pathogenesis and future efforts to develop NK cell-based therapeutic options.