# Discriminating EGFR function in T cells and epithelium during immune-mediated tissue damage

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $772,319

## Abstract

Interactions between the immune system and the intestinal stem cell (ISC) compartment are poorly understood,
as are the mechanisms by which ISCs respond to immune-mediated insults. In the previous R01 cycle, we made
several major discoveries: 1) T cells infiltrate and directly target the ISC compartment in vivo. 2) T cells mediate
Interferon-γ-dependent ISC killing in models of graft vs. host disease (GVHD) and autoimmunity. 3) Lymphocyte-
derived cytokines also target ISCs to promote JAK/STAT-dependent epithelial regeneration, and this
immunobiology can be translated clinically as demonstrated by our recently completed trial of Interleukin (IL)-22
treatment for patients with GVHD. 4) We have identified a new mechanism of epithelial regeneration whereby
ISC-derived IL-33 induces the stem cell niche to augment epidermal growth factor (EGF) production after
damage. Additionally, new unpublished data uncover the surprising finding that another EGF receptor (EGFR)
ligand, Amphiregulin (Areg), which is thought to promote epithelial regeneration, can signal directly to T cells,
drive their proliferation, and promote immune-mediated epithelial injury. Preliminary findings show that CD4 T
cells upregulate Areg and EGFR upon activation, increasing their expansion, tissue infiltration, ISC loss, and
intestinal pathology. The newly discovered IL-33-dependent epithelial regeneration pathway and our new data
identifying a pathologic role for the T cell Areg/EGFR axis in tissue damage present a critical translational conflict:
the IL-33/EGF regenerative circuit supports the therapeutic potential of EGF administration, but administering
EGFR ligands also has the potential to drive further immune-mediated damage by stimulating T cell EGFR.
The goals of this project are to investigate 1) the function of the EGFR pathway in activated T cells, 2) EGFR
function within the ISC compartment in models of immune-mediated tissue damage, and 3) how these pathways
can be targeted to reduce immune-mediated damage and enhance regeneration. Utilizing a combination of in
vivo and ex vivo T cell activation models, as well as ex vivo modeling of tissue responses to T-cell-mediated
damage using murine and human organoid culture systems, we will test the hypothesis that Areg produced by
activated CD4 T cells drives autocrine EGFR signaling and T cell proliferation, leading to tissue infiltration and
ISC compartment damage in the allogeneic setting. This represents a potential paradigm shift in the
understanding of Areg and EGFR. We will also test the hypothesis that ISCs respond to this damage by
enhancing the function of their own niche, identifying ISCs as not just the mediators but the regulators of
regeneration. This study will thus mechanistically uncouple pathologic T cell EGFR signaling from regenerative
epithelial EGFR signaling to enable rational design of novel therapies for protecting tissues from immune-
mediated damage and promoting epithelial regeneration. In collabor...

## Key facts

- **NIH application ID:** 10982147
- **Project number:** 2R01HL146338-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Alan M Hanash
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $772,319
- **Award type:** 2
- **Project period:** 2018-08-25 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10982147

## Citation

> US National Institutes of Health, RePORTER application 10982147, Discriminating EGFR function in T cells and epithelium during immune-mediated tissue damage (2R01HL146338-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10982147. Licensed CC0.

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