# Role of purinergic receptor P2X7 in the differentiation and function of iNKT cell subsets

> **NIH NIH P20** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2022 · $349,598

## Abstract

Metabolic reprogramming supports the differentiation, expansion and functional maturation of effector and 
memory T cells. It is also contributing to the de-regulation of T cell functions, such as T cell exhaustion in the 
tumor microenvironment, or break of tolerance in autoimmune diseases. Understanding how distinct metabolic 
programs are regulated to facilitate lineage specific development and function will provide important insight for 
designing new therapeutics targeting T cell metabolism. iNKT cells are a group of innate-like T cells, playing 
important roles in many pathological conditions. iNKT cell differentiation into mature functional subsets NKT1, 2 
and 17 in the thymus represents an alternative paradigm of T cell development. In our preliminary study, we 
have identified distinctive metabolic features of iNKT cell subsets, and the purinergic receptor P2X7 as a new 
regulator for iNKT cell differentiation. The overall goal of this study is to define the mechanism how P2X7 
modulates subset specialization and functional maturation. In Aim 1, we will determine the role of P2X7 as an 
ATP gated Ca2+ channel to promote optimal Ca2+ signals during iNKT cell differentiation. We will explore the 
connections between P2X7 and TCR activation, as well as Ca2+ as an important co-factor for mitochondria 
respiration. In Aim 2, we will define the role of P2X7 as a metabolic regulator during iNKT cell differentiation and 
activation. We will test if and how P2X7 regulates glucose metabolism, and if the energy sensor AMPK acts 
down stream of P2X7 activation. The immediate contribution of this study is to reveal novel metabolic 
components/processes, such as extracellular ATP (eATP, ligands for P2X7), Ca2+ signal, and mitochondria, 
which can specifically modulate iNKT subsets differentiation and effector functions. The support from a COBRE 
grant will enable us to take a critical step towards our long-term goal, targeting innate-like T cell metabolism 
to treat human diseases.

## Key facts

- **NIH application ID:** 10339355
- **Project number:** 5P20GM139763-02
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Meng Zhao
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $349,598
- **Award type:** 5
- **Project period:** 2021-02-05 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339355

## Citation

> US National Institutes of Health, RePORTER application 10339355, Role of purinergic receptor P2X7 in the differentiation and function of iNKT cell subsets (5P20GM139763-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10339355. Licensed CC0.

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