# Mitochondria regulate adaptive immunity

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $395,000

## Abstract

Abstract
T cells are major mediators of adaptive immune responses and resolution. Previously, we found that activated
T cells also increase their rate of mitochondrial oxygen consumption; and that in the absence of a critical
subunit of complex III within the electron transport chain, T cells failed to be activated in vitro or in vivo.
Further, we found that upon T regulatory cell (Treg cell) specific inactivation of complex III, Treg cells survived,
proliferated, and maintained stable Foxp3 expression but failed to function, resulting in a scurfy-like phenotype.
Our findings identified mitochondria as necessary regulators of essential conventional and regulatory T cell
functions. A central question based on our previous observations is how mitochondrial metabolism controls
both conventional T cell and regulatory T cell function. We propose that mitochondrial metabolism is
necessary for adaptive immune functions through the generation of ETC dependent reactive oxygen species
(ROS) and production of TCA cycle metabolites to control transcription factors and chromatin/DNA
modifications, respectively. Mitochondrial ETC complex I and III are the dominant sites of ROS generation.
TCA cycle enzymes can elevate the production of succinate and L-2-hydroxygluatrate (L-2HG) to control DNA
and histone methylation. Thus, we hypothesize that conventional CD8T cells require mitochondrial ROS for
activation and memory differentiation; but that maintenance of memory CD8 T cells requires TCA cycle
metabolites. Also, we postulate that mitochondrial TCA cycle metabolites control Treg suppressive function by
controlling DNA methylation. To test this hypothesis, we propose the following aims: Specific Aim I:
Determine whether complex I or III generated ROS are required for CD8 T cell activation, and memory
formation while TCA cycle metabolites are essential for memory maintenance. Specific Aim II: Determine
whether TCA cycle metabolites control Treg cell suppressive function. Together these aims will define the
mechanisms by which mitochondria dictate T cell fate and function.
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## Key facts

- **NIH application ID:** 10242090
- **Project number:** 5R01AI148190-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** NAVDEEP S CHANDEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,000
- **Award type:** 5
- **Project period:** 2019-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242090

## Citation

> US National Institutes of Health, RePORTER application 10242090, Mitochondria regulate adaptive immunity (5R01AI148190-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242090. Licensed CC0.

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