# Distinct functions of E protein family members in regulating γδ T lineage commitment and effector fate

> **NIH NIH P01** · RESEARCH INST OF FOX CHASE CAN CTR · 2020 · $313,566

## Abstract

PROJECT SUMMARY/ABSTRACT
T cells belonging to the gd-lineage have been shown to serve unique and critical roles within the immune system.
gd T cells are widely distributed throughout mucosal and epithelial cell-rich tissues and are an important early
source of IL-17, which recruits granulocytes to sites of inflammation in response to pathogens. However,
dysregulation of IL-17 production by gd T cells has also been linked to multiple pathological conditions including
autoimmune disease and cancer progression. Unlike conventional ab T cells, gd T cells can acquire the ability
to rapidly produce inflammatory cytokines within the thymus during development, prior to antigen exposure. The
molecular and cellular events that specify and assign gd T cells to the IL-17 (gdT17) or interferon-g (IFNg; gdT1)
effector fates during development remain to be fully elucidated. Recent evidence indicates that E proteins, in
particular HEB, are critical mediators of this fate choice. HEB transcription factors are encoded by the Tcf12
gene locus, which gives rise to two proteins, HEBAlt and HEBCan, that differ in their structure, transcription
initiation sites, and expression patterns. HEBAlt and HEBCan are expressed at partially overlapping times during
gd T cell development, but their respective roles in functional programming of gd T cell precursors are unclear.
We and others have identified a number of signaling pathways that contribute to gd T cell effector fate acquisition,
including those that operate through T cell receptor (TCR), Notch, and cytokine receptors. It is our goal to
understand how HEB activity is integrated with other determinants of gd T cell programming. Given our recent
finding that HEB factors are required for the development of gdT17, but not gdT1 cells, we hypothesize that the
final differentiation and effector function programming of gd T cells is directed by the interplay of specific HEB
and E2A proteins with transcriptional regulators downstream of TCR, Notch, and cytokine receptor signaling. We
will take advantage of a new in vitro model system that directs fate bifurcation between the gdT1 and gdT17 fates,
as well as novel mouse models that we have generated, to elucidate the roles for E protein dimers containing
HEBAlt, HEBCan, and/or E2A in determining gd T cell effector function, and to gain insight into the molecular
basis for these events by assembling global gene regulatory networks. Our aims are: 1) to define the roles of
HEBAlt, HEBCan, and E2A in intrathymic gd T cell differentiation by identifying specific target genes and
binding partners in WT and mutant mice; and, 2) to evaluate the roles of HEB factors and their targets in
human gd T cell development. Our proposal is built upon key observations derived from all Program Projects.
The proposed experiments will continue to draw the complementary expertise in the areas of TCR signaling
(Proj.1), mouse genetics (Proj.2), and chromatin remodeling (Proj.4). Our specific aims will...

## Key facts

- **NIH application ID:** 9989063
- **Project number:** 5P01AI102853-07
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Juan Carlos Zuniga-Pflucker
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $313,566
- **Award type:** 5
- **Project period:** 2014-05-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989063

## Citation

> US National Institutes of Health, RePORTER application 9989063, Distinct functions of E protein family members in regulating γδ T lineage commitment and effector fate (5P01AI102853-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9989063. Licensed CC0.

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