# ID3 regulation of tissue-infiltrating T cells mediating graft-versus-host disease and leukemia rejection

> **NIH NIH R01** · HACKENSACK UNIVERSITY MEDICAL CENTER · 2024 · $752,830

## Abstract

PROJECT SUMMARY
Graft-versus-host disease (GVHD) and the sequelae of immunosuppression have been a major barrier to the
success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which can potentially cure
hematological cancers such as leukemia, lymphoma and myeloma. GVHD is caused by donor T cells that attack
recipient’s non-hematopoietic-lymphoid tissues (non-HLTs), including gastrointestinal (GI) tract, liver and skin.
Advanced strategies with more aggressive immunosuppression agents can better control GVHD. Consequently,
cancer relapse becomes the major cause of deaths (>50%) in allo-HSCT patients. Persisting alloreactive donor
T cells in non-HLTs are known a determinant of GVHD. Indeed, we recently discovered that inhibition of
RIPK1/RIPK3 activity in the GI tract reduces both local and systemic GVHD. These observations together with
others highlight an urgent need of better defining how GVHD is locally maintained. A hallmark of tissue-infiltrating
alloreactive T cells is their capacity to persist and function in response to persistent alloantigens. They show
tissue-resident memory T cell features, contain a subset of Tcf1+ progenitor-like T cells (Tcf1+ TPRO) with a great
ability to self-renew, and have acquired unique transcriptional programs for local tissue residence. However, the
transcriptional regulators that control these processes remain poorly defined. We recently demonstrate that Id3,
a transcription regulator important for CD8+ T cell memory response, has dual functions in maintaining
alloreactive T cell responses during GVHD. Id3 restrains excessive PD-1 expression and effector differentiation
of alloreactive T cells, but promotes the persistence of both Th1 effector T cells and Tcf1+ TPRO cells that infiltrate
non-HLTs. Donor T cells lacking Id3 fail to mediate severe GVHD. PD-1 blockade restores the capacity of Id3-
ablated donor T cells to induce GVHD. Id3 represses expression of transcription factors, which promote PD-1
transcription and exuberant effector differentiation of activated T cells, but sustains expression of Tcf1 protein,
which is required for self-renewal of memory T cells. Building on these findings, we hypothesize that Id3
regulates the formation and maintenance of tissue-infiltrating Tcf1+ TPRO cells that are critical for GVHD
maintenance and leukemia control through coordinating the expression of genes engaged in effector
differentiation and memory T cell development. Two specific aims are proposed to test this hypothesis. Aim 1
will define the effect of alloreactive Tcf1+ TPRO cells in GVHD maintenance and leukemia control and characterize
the central role of Id3 in these T cells. Aim 2 will establish the beneficial effects of ID3-engineered chimeric
antigen-receptor (CAR) T cells on eliminating leukemia. Our findings will provide novel molecular insights into
biology of tissue-infiltrating alloreactive T cells and lead to novel Id3 targeting-based non-HLT-specific
approaches to reduce GVHD ...

## Key facts

- **NIH application ID:** 10904278
- **Project number:** 1R01CA290808-01
- **Recipient organization:** HACKENSACK UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Hai-Hui Xue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $752,830
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904278

## Citation

> US National Institutes of Health, RePORTER application 10904278, ID3 regulation of tissue-infiltrating T cells mediating graft-versus-host disease and leukemia rejection (1R01CA290808-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10904278. Licensed CC0.

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