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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $760,808

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10707310
- **Project number:** 5R01AI169070-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JILL Allison HOLLENBACH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $760,808
- **Award type:** 5
- **Project period:** 2022-09-19 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10707310

## Citation

> US National Institutes of Health, RePORTER application 10707310, Role of Natural Killer Cell Diversity in Multiple Sclerosis Risk and Disease Course (5R01AI169070-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10707310. Licensed CC0.

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