# Intrinsic modulators of Treg lineage commitment and immunoregulation post-transplantation

> **NIH NIH R00** · BOSTON CHILDREN'S HOSPITAL · 2021 · $249,000

## Abstract

Allograft rejection is mediated by the recipient’s immunological response to donor antigen that is
initiated and coordinated by CD4+ T cells, but it also involves other complex issues including
adaptive responses within secondary lymphoid organs and within the graft itself. CD4+Foxp3+
regulatory T cells (Treg) are central to the maintenance of self-tolerance, the regulation of
excessive immune responses, and experimental therapies use their immunoregulatory
properties to suppress alloimmunity and to induce immunological tolerance towards the
allograft. However, Treg based therapies are hindered by their instability and their potential to
dedifferentiate into effector cells that can initiate/cause rejection. Our previous studies
demonstrated that DEPTOR is expressed by CD4+ Treg cells, is markedly reduced upon mitogen
activation, and that sustained expression of DEPTOR stabilizes lineage commitment via the
epigenetic regulation of the Foxp3 promoter and by augmenting oxidative metabolism. In vivo, induced
DEPTOR expression within Tregs is sufficient to promote immunoregulation and inhibit cardiac
allograft rejection. This proposal tests the hypothesis that DEPTOR is a central modulator of Treg
subset homeostasis and function, and that it is essential to maintain immunoregulation and tolerance
following transplantation. It will also test whether DEPTOR functions via a novel regulatory signaling
network and/or novel interactions with target genes within distinct Treg lineages or subsets. The
approach is divided into three specific aims to: first, investigate mechanisms of DEPTOR function in
Tregs and mTOR-independent targets of DEPTOR activity; second, systematically discover the
extended DEPTOR-induced modulatory signaling network that enhances Treg function and lineage
commitment; and third, identify small molecules that modulate DEPTOR protein expression, its
downstream target genes and/or regulatory signaling activity as potential pro-tolerogenic therapeutic
drugs. During the mentored phase of the K99, the results of the proposed studies will identify new
roles for DEPTOR in Treg subsets and discover mTOR-independent effects of DEPTOR on Treg
biology. These studies will launch the R00 phase of independent research to investigate the
mechanistic function of the network of negative modulators and/or target genes in Treg subsets, and
develop a pharmacological screening assay to identify small molecules that have potential as
therapeutic drugs to induce immunological tolerance towards allografts and/or as a treatment for
autoimmune disease. The broader implication of this work relates to the biological importance of
Treg targeting as a component of tumor immunotherapy.

## Key facts

- **NIH application ID:** 10436409
- **Project number:** 4R00AI146279-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Johannes Wedel
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2021-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436409

## Citation

> US National Institutes of Health, RePORTER application 10436409, Intrinsic modulators of Treg lineage commitment and immunoregulation post-transplantation (4R00AI146279-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10436409. Licensed CC0.

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