# The role of TIGIT in Treg-mediated suppression of C8+ T cells in Transplantation

> **NIH NIH F31** · EMORY UNIVERSITY · 2022 · $46,752

## Abstract

Summary/Abstract
Transplantation is a curative strategy for end stage organ failure. In order to avoid immune-mediated rejection
of the grafted tissue, recipients receive life-long immunosuppression. Calcineurin and mTOR inhibitors for
immunosuppression are successful in preventing graft rejection but are associated with significant adverse off-
target toxicities. In order to better preserve the health of both the graft and the transplant recipient, alternative
immunosuppressive therapies have been sought. Belatacept, a CTLA-4Ig fusion protein, suppresses the
immune system by binding to CD80 and CD86 on antigen presenting cells (APCs) to block CD28
(costimulatory) and CTLA-4 (coinhibitory) signaling on T cells. By blocking interactions that are specific for
immune cells, the use of CTLA-4Ig mitigates off-target toxicities associated with calcineurin inhibitors and
increases the longevity of the graft and health of the patient. However, CTLA-4Ig is associated with increased
risk of acute rejection episodes compared to calcineurin inhibitors, which has prohibited its widespread clinical
adoption despite the improved long-term outcomes. Regulatory T cells are essential to maintaining immune
homeostasis and promoting tolerance in transplant, but the blockade of signaling through CD28 and CTLA-4 is
detrimental to their survival and function. Therefore, CTLA-4Ig therapy inhibits Tregs from controlling CD8+ T
cells as they execute acute rejection. Identifying costimulatory and coinhibitory pathways that can be targeted
to enhance the suppressive capacity of Tregs in the setting of CTLA-4Ig therapy is essential to improving
targeted immunosuppressive therapies. TIGIT is a T-cell inhibitory receptor with Ig and ITIM domains
expressed on Tregs that can be targeted with antibodies to fine-tune Treg function. Agonistic anti-TIGIT
antibodies have been shown to induce apoptosis of costimulation blockade-resistant memory T cells in a Treg-
dependent manner. The experiments outlined in this proposal study the mechanisms by which TIGIT signaling
on Tregs enhances Treg function in the face of CTLA-4Ig therapy to reduce CD8 + T cell responses to allograft
challenge. In Aim 1 we will determine if cell-autonomous TIGIT signaling increases the abundance of Tregs
within grafted tissue and increases the secretion of suppressive molecules to enhance Treg function. In Aim 2
we will determine the impact of Treg-specific TIGIT signaling on effector CD8+ T cell responses to allograft.
These studies will be performed using novel Treg-specific TIGIT knockout animals (Foxp3-Cre x TIGITfl/fl).
Together, these data will illuminate the therapeutic potential of TIGIT agonism in combination with
costimulation blockade therapeutics to mitigate acute allograft rejection.

## Key facts

- **NIH application ID:** 10466064
- **Project number:** 1F31AI161911-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Christina Rose Hartigan
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466064

## Citation

> US National Institutes of Health, RePORTER application 10466064, The role of TIGIT in Treg-mediated suppression of C8+ T cells in Transplantation (1F31AI161911-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10466064. Licensed CC0.

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