# Immunological Synapse Restricted Metabolic Reprogramming Drives Driectional Cytokine Synthesis

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $46,036

## Abstract

Project Summary/Abstract
 T cells become activated when they encounter an antigen presenting cell and receive three signals: TCR
signaling via peptide-MHC, co-stimulatory signaling and cytokines. Activation drives a host of metabolically
demanding processes such as proliferation, differentiation, migration, and effector functions. Thus, T cells switch
from oxidative phosphorylation (OXPHOS), when naïve, to aerobic glycolysis upon activation to generate enough
ATP to accommodate these processes. We recently showed that T cells engage aerobic glycolysis within
minutes of TCR signaling, independent of co-stimulatory signaling. We found that this mechanism was mediated
by pyruvate dehydrogenase kinase 1 (PDHK1), a mitochondrial enzyme that associated with LCK and migrated
to the T cell synapse upon activation. These data suggested that aerobic glycolysis could be spatially regulated
at the T cell synapse during activation. Using pH sensitive fluorescent systems, we were able to generate data
visualizing aerobic glycolysis restricted to the T cell synapse. These data suggest that the mitochondrial
positioning in T cells could regulate the initiation of aerobic glycolysis at the immunological synapse. Further, our
lab and others have shown that glycolytic enzymes, GAPDH and LDH, are mRNA binding proteins and repress
their cytokine translation in naïve T cells, and activation of glycolysis via TCR stimulus promotes the dissociation
of glycolytic enzymes from cytokines mRNA. Therefore, we hypothesize that mitochondrial migration to the
IS, regulated by mitochondrial LCK, enables localized aerobic glycolysis and subsequent synapse
restricted cytokine translation for directed effector functions. To address this hypothesis we will, (1) Identify
the role of mitochondrial LCK in driving mitochondrial migration to the T cell synapse and the initiation of aerobic
glycolis. Using pH sensitive fluorescence systems, and mitochondrial and LCK reporters, we will visualize the
dynamics of aerobic glycolysis, mitochondria and LCK at the T cell synapse when TCR is stimulated by an APC.
Moreover, we will (2) Investigate the role of site restricted aerobic glycolysis in promoting localized cytokine
translation at the T cell synapse. Using modulators of glycolytic metabolism, we will determine whether aerobic
glycolysis could enhance the production of effector cytokines in activated T cells, and whether aerobic glycolysis
predicts sites where cytokines are being translated. By better understanding the early signals that promote
metabolic reprogramming and drive effector functions we can develop therapeutic targets that will allow
us to metabolically modulate T cell activity.

## Key facts

- **NIH application ID:** 10156024
- **Project number:** 1F31AI152429-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ronal Peralta
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2022-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10156024

## Citation

> US National Institutes of Health, RePORTER application 10156024, Immunological Synapse Restricted Metabolic Reprogramming Drives Driectional Cytokine Synthesis (1F31AI152429-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10156024. Licensed CC0.

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