# Genetic determinants of NK cell function

> **NIH NIH P01** · UNIVERSITY OF MINNESOTA · 2020 · $250,414

## Abstract

Natural killer (NK) cells are a major lineage of human lymphocytes with vital functions in innate immunity, 
adaptive immunity and hematopoietic cell transplantation. These functions are mediated by the diverse 
interactions of highly polymorphic HLA-A, -B, and -C molecules with equally polymorphic killer immunoglobulin- 
like receptors (KIR). They are complemented by the conserved interactions of HLA-E with CD94:NKG2 
heterodimers. The genes encoding KIR receptors and HLA ligands segregate independently, thereby 
generating unique and diverse genotypes within families and populations. Phenotypically, this produces 
functionally distinct NK-cell repertoires, a natural variation that has profound effects on susceptibility to 
infection and autoimmunity, on reproductive success, and the outcome of HCT. In SA1 we will extend 
retrospective statistical analyses of KIR and HLA variation in HCT to the highest levels of allele-level resolution 
and precision. We have developed a novel target capture and next-generation sequencing methodology with 
compatible bioinformatics tools. These will be used to determine complete KIR haplotype sequences and 
define allelic and allotypic variation throughout the KIR locus. In SA2 we will perform high-resolution analysis of 
immune reconstitution following HCT. Three cohorts will be studied -- HLA-matched, HLA-mismatched, and 
HLA-haploidentical transplants – by comparing the mature NK cells of the donor to the reconstituting NK cells 
in the transplant recipient. Longitudinal differences in immune phenotype will be assessed and compared. 
Functional capacity of the NK cells will be tested by challenge with target cells expressing self, altered-self, 
non-self and missing-self HLA class I. Early, intermediate and late stages in immune system reconstitution will 
be evaluated. We will assess the reconstituted NK-cell response to exogenous stimuli (the CD16 directed- 
BiKEs and IL-15/IL-15Rα-Fc superagonist complexes also studied in Projects 2 and 3) at the different stages. 
All analyses will consider KIR and HLA genotypes and CMV status. NK cells mature to acquire functional 
immunity through a process called education. SA3 of this project will analyze mature, educated NK cells and 
determine their functional capacity to recognize and respond to target cells expressing self, non-self, altered- 
self, and missing-self HLA class I. To achieve this goal, we will develop a high-throughput assay to assess NK- 
cell responses to an extensive cell panel, in which each member cell expresses a different HLA class I 
allotype. From these data, predictive rules for education, based on the KIR and HLA genotype and CMV status 
of individuals, will be defined. Mass cytometry will be used to analyze NK cells and other lymphocyte 
subpopulations for individuals with selected combinations of KIR, HLA and CMV status. The results from this 
project will exponentially increase knowledge of the genetic factors influencing the outcome o...

## Key facts

- **NIH application ID:** 9905399
- **Project number:** 5P01CA111412-15
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** PETER R PARHAM
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $250,414
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905399

## Citation

> US National Institutes of Health, RePORTER application 9905399, Genetic determinants of NK cell function (5P01CA111412-15). Retrieved via AI Analytics 2026-06-05 from https://api.ai-analytics.org/grant/nih/9905399. Licensed CC0.

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