# Role of DEPTOR in T Cell Activation and Alloimmunity

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $575,250

## Abstract

Project Summary/Abstract
Allograft rejection is characterized by effector CD4+ T cell activation in response to donor antigen and an
intense cellular and humoral attack on the graft. However, multiple intracellular signals within CD4+ T cells
operate co-incidentally to enhance the expansion and function of CD4+Foxp3+ T regulatory cells that
collectively serve to control the alloimmune response. Furthermore, the potency of this process of
immunoregulation prevents and restrains alloimmune T effector cell activation and rejection. Importantly,
recent advances indicate that CD4+Foxp3+ T cell differentiation and function is negatively regulated by the
cell intrinsic activity of mTOR and specifically mTORC1. However, little is known about the regulation of
intracellular mTOR signaling within alloreactive CD4+ T cell effectors, or how its relative activity may be
modulated in Foxp3+ subsets, or whether it is possible to exploit modulatory signals to augment
physiological Treg activity in pathological states to prevent disease, including the development of chronic
allograft rejection. DEPTOR is a recently discovered cell intrinsic factor that modulates mTOR-induced
signaling responses in highly proliferative cancer cells, and it has more recently been observed to function
in normal cell types including vascular endothelial cells. In preliminary studies, we find that DEPTOR is
expressed at high levels in unactivated CD4+ T cells, and further, that its expression is reduced upon
cellular activation. In addition, we find that forced overexpression of DEPTOR modulates CD4+ T cell
activation responses in vitro, promotes immunoregulation and prolongs graft survival following fully MHC
mismatched transplantation in vivo. We suggest that these observations identify DEPTOR as a critical
upstream intracellular modulator of CD4+ T cell activation as well as the phenotypic and functional outcome
of the alloimmune response. Our objectives in this R01 are to further evaluate these observations using
novel transgenic mice, and 1), define the select function of DEPTOR in CD4+ T effector and regulatory
subsets in vivo, and 2), evaluate the consequences of CD4+ T cell DEPTOR expression in models of
transplant rejection. We will test the hypothesis that DEPTOR is a cell intrinsic molecule that modulates
CD4+ T effector cell activation and augments CD4+ T regulatory cell function to enhance immunoregulation
and promote long-term graft survival. We propose two specific aims in which we will: 1), determine the
consequences and mechanism of function of cell intrinsic DEPTOR in CD4+ T cell subsets, and 2),
determine the function of CD4+ T cell DEPTOR in long-term allograft survival. Collectively, these innovative
studies will have broad scientific and biological implications of great significance and relevance to
transplantation immunobiology.

## Key facts

- **NIH application ID:** 10302288
- **Project number:** 5R01AI136503-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** David M. Briscoe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $575,250
- **Award type:** 5
- **Project period:** 2017-12-08 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10302288

## Citation

> US National Institutes of Health, RePORTER application 10302288, Role of DEPTOR in T Cell Activation and Alloimmunity (5R01AI136503-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10302288. Licensed CC0.

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