# Understanding the influence of SREBP signaling on CD4 T helper cell biology

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $385,000

## Abstract

PROJECT SUMMARY
This application is focused on understanding the molecular mechanisms underlying reprogramming of lipid
metabolism in CD4 T helper subsets, and assessing the impact of sterol metabolism on T helper cell function.
Accumulating evidence indicates that CD4 T helper cells rapidly change their metabolic state in response to
TCR activation and cytokine signals. This reprogramming is necessary to match the bioenergetic and
biosynthetic requirements of specific effector functions. In general pro-inflammatory CD4 T cells (e.g., Th1 and
Th17) acquire a robust glycolytic program, and shift their metabolism towards an anabolic state. In contrast,
regulatory T cells are largely reliant on fatty acid oxidation and macromolecule catabolism to meet their
bioenergetic and biosynthetic requirements. This distinction in metabolic programming appears to be essential
for proper T helper cell function. Genetic or pharmacologic manipulation of a T helper cell's metabolic state
can attenuate or exacerbate specific effector functions. For example, enforcing a glycolytic program perturbs
the suppressive ability of Tregs, and results in a loss of self-tolerance in models systems. In contrast, enforcing
fatty acid oxidative metabolism downregulates the pro-inflammatory function of Th1 and Th17 cells, thereby
attenuating disease pathogenesis. These observations have led to the concept that a CD4 T helper cells
metabolic state is a fundamental component of the effector program. Despite the clear importance of acquiring
and maintaining the appropriate metabolic state, the molecular mechanisms underlying how distinct T helper
cells acquire the requisite metabolic programs remain poorly understood. In recent work we have identified the
sterol regulatory element binding proteins (SREBP1 and 2) as critical regulators of metabolic reprogramming in
CD8 T cells. Mechanistic studies revealed that SREBPs are activated by TCR signals and drive acquisition of
glycolysis and anabolic metabolism. In the absence of SREBP activity, we found that CD8 T cells were unable
to upregulate glycolytic flux and synthesis of lipids, resulting in poor proliferative capacity and attenuated
effector responses. These data have led us to hypothesize that SREBPs would play a critical function in
regulating the CD4 T helper subset differentiation and effector function. In support of this hypothesis, we find in
preliminary data that attenuation of the SREBP program selectively perturbs the in vitro differentiation of Th1
and Th17 cells, but does not influence induction of regulatory T cells, nor does it influence the
generation/homeostasis of Foxp3-positive Tregs in vivo. Thus, we conclude that SREBP signaling plays an
important and previously undefined role in controlling the balance of T helper subsets. In this application, we
extend on these intriguing preliminary data and propose three integrated aims designed to elucidate the
molecular mechanism(s) by which SREBPs influence T helper cell ...

## Key facts

- **NIH application ID:** 9812828
- **Project number:** 5R01AI122282-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** STEVEN J BENSINGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2015-11-10 → 2020-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9812828

## Citation

> US National Institutes of Health, RePORTER application 9812828, Understanding the influence of SREBP signaling on CD4 T helper cell biology (5R01AI122282-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9812828. Licensed CC0.

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