# Bidirectional metabolic signaling in follicular helper T cell differentiation

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $536,278

## Abstract

Program Summary/Abstract
Follicular helper T (Tfh) cells provide essential help for B cells and high-affinity antibody production, thereby
linking cellular and humoral immunity. While much emphasis has been placed on immune receptors (e.g.
ICOS) and transcription factors (e.g. Bcl6) required for Tfh differentiation, how signals are transduced from
receptors to transcriptional and biological responses remains poorly defined. Emerging studies reveal nutrient
signaling and metabolic reprogramming as fundamental processes underlying the growth and fate decisions of
activated lymphocytes. However, many questions remain regarding the specific metabolic pathways important
for T cell fate decisions (rather than as a consequence of changes in cellular phenotypes), and how immune
signals intersect with nutrient inputs and metabolic programs. For instance, compared with our knowledge on
glycolytic or Warburg metabolism, the function and regulation of mitochondrial metabolism are much less clear.
We establish that mTOR acts as a key driver of Tfh differentiation by coordinating T cell receptor and ICOS
signaling and glucose metabolism. Through unbiased screens, mouse genetic models and systems biology
approaches in our preliminary studies, we also revealed crucial roles of nutrient signaling and mitochondrial
metabolism in Tfh responses. Our central hypothesis is that the interplay between mTORC1 and nutrient
signaling pathways and mitochondrial metabolic programs orchestrates bidirectional metabolic
signaling and Tfh differentiation. Specifically, we will (1) identify the mechanisms that integrate nutrient and
immune signals in Tfh responses, and (2) establish mitochondrial function and metabolic heterogeneity in Tfh
responses. Importantly, despite the emerging interest in immunometabolism, how nutrient signaling and
mitochondrial metabolism contribute to T cell function remains poorly understood. Building upon our expertise
and innovation that combine genetic and systems biology approaches, we will address fundamental questions
of immunometabolism and Tfh biology. Insights gained from this application may significantly impact our
understanding of Tfh biology and manifest legitimate therapeutic opportunities.

## Key facts

- **NIH application ID:** 10466976
- **Project number:** 5R01AI150241-04
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Hongbo Chi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $536,278
- **Award type:** 5
- **Project period:** 2019-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466976

## Citation

> US National Institutes of Health, RePORTER application 10466976, Bidirectional metabolic signaling in follicular helper T cell differentiation (5R01AI150241-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10466976. Licensed CC0.

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