# Promoting T cell reconstitution after hematopoietic cell transplantation

> **NIH NIH R35** · FRED HUTCHINSON CANCER CENTER · 2024 · $1,195,546

## Abstract

PROJECT SUMMARY
 The thymus, which is the primary site of T cell generation, is extremely sensitive to injury; but also has a
remarkable capacity for endogenous repair. However, even though there is continual thymic involution and
regeneration in response to everyday insults like stress and infection, profound thymic damage caused by
common cancer therapies and the conditioning regimes for hematopoietic cell transplantation (HSCT) lead to
prolonged T cell lymphopenia. Furthermore, in the context of allogeneic HCT, the thymus is an extremely
sensitive target to alloreactive T cells during graft versus host disease (GVHD). Consequently, identification of
therapies that can boost T cell reconstitution in recipients of HSCT is a clinical priority.
 We have previously identified two distinct pathways of endogenous thymic regeneration, centered on the
production of the regeneration factors IL-22 by innate lymphoid cells (ILCs), and BMP4 by endothelial cells (ECs);
both of which mediate their regenerative effects by targeting thymic epithelial cells (TECs). More recently we
have found that the trigger for these distinct regenerative pathways hinge on the balance between forms of cell
death, with immunologically silent apoptosis (which is abundant in thymocytes during steady-state) suppressive
to the regenerative program. On the other hand, after thymic damage caused by radiation injury, we found a
switch toward immunogenic cell death, with the resulting release of damage-associated molecular patterns
(DAMPs) sufficient to promote regeneration. Specifically, we identified that intracellular Zn was released after
radiation injury, where it could signal through the G-protein coupled receptor 39 (GPR39) to stimulate production
of BMP4 and IL-23, a key upstream regulator of IL-22 production. Separately, we also found that the release of
the prototypical DAMP, ATP, was able to signal directly on thymic epithelial cells through purinergic (P2)
receptors and promote their expression of Foxn1, key microenvironmental drivers of T cell development.
Importantly, our preliminary data also suggests that each of these pathways can be therapeutically targeted to
improve thymic recovery in mouse models of HCT. Our preliminary data has also identified putative TEC
precursors that are important for regenerating the epithelial compartment and thus promoting regeneration, as
well as the emergence with age of aberrant epithelial cells that limit thymic function, including in its reparative
capacity after acute damage. Our research program is thus exploring several key questions: What are the
triggers and upstream regulators of endogenous tissue regeneration in the thymus? Which cells mediate tissue
regeneration in the thymus after acute injury? Are there limitations to endogenous regeneration after HCT across
sex and lifespan? Can we exploit these mechanisms of endogenous regeneration to develop therapeutic
strategies to boost T cell reconstitution in HCT recipients?
 The st...

## Key facts

- **NIH application ID:** 10789742
- **Project number:** 1R35HL171556-01
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Jarrod Dudakov
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,195,546
- **Award type:** 1
- **Project period:** 2024-01-01 → 2030-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789742

## Citation

> US National Institutes of Health, RePORTER application 10789742, Promoting T cell reconstitution after hematopoietic cell transplantation (1R35HL171556-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10789742. Licensed CC0.

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