# Understanding T cell susceptibility to regulatory T cell-mediated suppression

> **NIH NIH R21** · UNIVERSITY OF VIRGINIA · 2020 · $197,222

## Abstract

Abstract
 Immune tolerance is a multifaceted process, mediated by central and peripheral
tolerance, and often resides in a tenuous balance between positive and negative signals. For
T cells, central tolerance occurs in the thymus, where negative selection leads to deletion of
potentially auto-reactive T cells. On the other hand, peripheral tolerance occurs at many
levels, one of which is mediated by a specialized subtype of T cells, the regulatory T cells
(Treg). In autoimmune/ auto-inflammatory diseases, this balance is shifted towards T cell
activation and effector function versus Treg-mediated T cell suppression. While qualitative
or quantitative defects in Treg cells are a possible cause for autoimmune diseases, over the
last 10 years increasing evidences from mouse models and human studies suggest that
conventional T cells can become refractory to Treg suppression. However, the underlying
mechanisms regulating susceptibility to Treg suppression are still poorly understood.
Because of the clinical implications, not just for autoimmune diseases but also for anti-tumor
immunity, where Treg suppression is still major obstacle, we need additional insights on
brakes and accelerators that control T cell responsiveness.
 Our laboratory has been investigating one of the brakes, the protein tyrosine phosphatase
SHP-1, for many years. We have recently identified a new role of SHP-1 in peripheral
tolerance. Specifically, T cells lacking SHP-1, display resistance to Treg-mediated
suppression both in vitro and in vivo. Here, we hypothesize that loss of SHP1 in conventional
T cells causes `qualitative differences' in their functionality that renders them resistant to
Treg suppression. Although we are excited about the possible implications of having
identified an intracellular signaling molecule that directly affects the responsiveness of a T
cell to Treg-mediated suppression, we are now at an intellectual crossroad, necessitating this
R21 application. We would like to distinguish - does the resistance of T cells lacking SHP-1
arise from altered early signaling events resulting in a short-term stunting of dampening
signals (Aim 1) and/or is this a long-term reprogramming of the T cells in response to SHP-1
deficiency (Aim 2)? To address these possiblitites, we take several unbiased approaches,
which are critically needed and form the basis for this application. We believe these studies
will be broadly relevant for understanding how conventional non-regulatory T cells respond to
Treg-mediated suppression, and will guide us in future research directions.

## Key facts

- **NIH application ID:** 9949630
- **Project number:** 5R21AI139967-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Ulrike Lorenz
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $197,222
- **Award type:** 5
- **Project period:** 2019-06-12 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949630

## Citation

> US National Institutes of Health, RePORTER application 9949630, Understanding T cell susceptibility to regulatory T cell-mediated suppression (5R21AI139967-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9949630. Licensed CC0.

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