# E protein targets orchestrating γδ development and function

> **NIH NIH P01** · RESEARCH INST OF FOX CHASE CAN CTR · 2020 · $598,284

## Abstract

PROJECT SUMMARY/ABSTRACT
T lymphocytes comprise two major lineages,  and , which play critical, partially-distinct roles in host defense.
 and  T cells arise from a common progenitor in the thymus; however, the molecular processes responsible
for specification of these lineages during development in the thymus remain unclear and this represents a major
gap in knowledge. We seek to address this knowledge gap. In doing so, we have provided compelling evidence
that specification of the  and  T cell fates is controlled by differences in T cell receptor (TCR) signal strength.
These signaling differences regulate fate by proportional induction of Id3, which causes graded repression of the
function of E box DNA binding proteins (E proteins; E2A and HEB). To gain insight into how E protein binding to
the genome is remodeled during fate specification, we (all Projects) employed a comprehensive, genome-wide
approach, which revealed a number of important insights. First, the repression of E protein family members by
strong TCR signals is selective, in that E2A binding to the genome is markedly repressed, while HEB binding is
preserved (all Projects). Importantly, the sparing of HEB binding appears to be important, as HEB function is
required for development of  T cells that produce IL-17 (Proj1/3/4). Second, E protein binding is closely
associated with non-coding transcription, including long non-coding RNAs (lncRNA; all Projects). Indeed, we
(Projects 1 and 4) demonstrated that one such lncRNA, ThymoD, plays an essential role in T lineage
commitment. Finally, from among the numerous regulatory elements whose occupancy by E proteins is
modulated during  lineage commitment, we have already identified two that play critical roles in controlling 
development and function. Indeed, disruption of E protein binding to regulatory elements controlling the
expression of either transcription factor Tcf7 or lncRNA Gm15417 enhances  T cell maturation and promotes
adoption of the IL-17 producing effector fate. Consequently, in the current proposal, we integrate all of these
insights to elucidate the mechanistic basis by which changes in E protein binding to these elements controls
development of IL-17 producing  T cells. Insight into the factors controlling development of IL-17 producing 
T cells is critical, as these cells have been implicated in numerous immune-mediated pathologies and cancer
progression. To execute this research plan, we are entirely dependent upon the expertise of the Project Leaders
in the program, as well as Genomics Core B. This effort promises to provide great insight into the role of E
proteins in controlling both  development and function, which is of critical importance to human health and
disease.

## Key facts

- **NIH application ID:** 9989060
- **Project number:** 5P01AI102853-07
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** DAVID L. WIEST
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $598,284
- **Award type:** 5
- **Project period:** 2014-05-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989060

## Citation

> US National Institutes of Health, RePORTER application 9989060, E protein targets orchestrating γδ development and function (5P01AI102853-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9989060. Licensed CC0.

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