# Functional genetics of human innate immunity in the bimodal gamma delta T cell response to Epstein-Barr Virus and in education of NK cells and their re-education to respond to autologous cells

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $391,250

## Abstract

This project investigates how human genetic variation diversifies innate immune responses to infection and
cancer. Aim 1 concerns innate immunity to Epstein-Barr Virus (EBV), a cause of cancer. We found humans
form two equally sized groups based on their response to EBV. Group 1 make strong Natural Killer (NK) cell
and Vγ9Vδ2 T cell responses, whereas Group 2 combine a vigorous NK cell response with a poor Vγ9Vδ2 T
cell response. This difference does not correlate with sex, HLA type, prior exposure to EBV or CMV,
abundance of Vγ9Vδ2 T cells, or their functionality in the two groups. We propose that this even balance of
responders and non-responders arises because of costs and benefits in making a Vγ9Vδ2 T cell response to
EBV. Genetic precedents from our previous work are functionally distinctive haplotypes of both the killer cell
immunoglobulin-like receptor (KIR) gene family, and the HLA class I gene family. We will determine genetic
and functional differences that distinguish Group 1 and 2 donors, with three approaches. First, we will define
the γδ T cell receptor repertoires for resting and EBV-activated γδ T cells of Group 1 and 2 donors. Second, we
will define the phenotype and function of EBV-responding Vγ9Vδ2 T cells and NK cells in Group 1 and 2
individuals. Third, the γδ T cells of Group 1 and 2 individuals will be compared by high throughput RNA
sequencing. Aim 2 examines NK cell and γδ T cell crosstalk in response to EBV. Our preliminary data shows
that γδ T cells have an inhibitory effect on NK cell function in the context of EBV, and that this effect is distinct
in Group 1 vs Group 2 donors. We propose an examination of NK cell and γδ T cell crosstalk that incorporates
both NK cell educational status, and the dichotomous γδ T cell responses to EBV. Aim 3 examines interactions
between KIR and HLA-A, B and C that control NK cell development and responses to infected or malignant
cells that have low expression of HLA class I. These interactions involve four HLA class I epitopes and four
inhibitory KIR (iKIR). The polymorphism of KIR and HLA, their independent segregation and stochastic KIR
expression, mean that most humans express ligands without receptors and vice versa. During development,
NK cells expressing an HLA epitope and its cognate iKIR, become educated to kill cells that lack the epitope.
Consequently, educated NK cells can instigate a graft-versus-tumor (GVT) response in leukemia patients
following allogeneic hematopoietic cell transplant. The GVT response clears residual tumor cells and improves
patient survival. Preliminary experiments demonstrate that NK cells can be re-educated in vitro to kill malignant
cells. We will determine the potential for re-education in a donor cohort representing all 12 common genetic
combinations of the 4 HLA epitopes. This will give new insight on NK cell education and provide the foundation
for re-educating autologous NK cells as immunotherapy for leukemia. In summary, this work will define...

## Key facts

- **NIH application ID:** 9864030
- **Project number:** 5R01AI136952-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** PETER R PARHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,250
- **Award type:** 5
- **Project period:** 2019-02-05 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864030

## Citation

> US National Institutes of Health, RePORTER application 9864030, Functional genetics of human innate immunity in the bimodal gamma delta T cell response to Epstein-Barr Virus and in education of NK cells and their re-education to respond to autologous cells (5R01AI136952-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9864030. Licensed CC0.

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