# Reprogramming Double Negative T Cells to Combat Autoimmune Ovarian Failure and Ovarian Tumors

> **NIH HD R00** · UNIVERSITY OF FLORIDA · 2026 · $248,976

## Abstract

PROJECT SUMMARY (See instructions): 
Double-negative T cells (DNTs), characterized by the absence of CD4 and CDB expression but the 
presence of aBeta T cell receptors (TCRs), play a pivotal role in regulating immune homeostasis within the 
ovary and uterus. However, how the origin and function of DNTs in the ovary and reproductive tract 
remains poorly understood, representing a critical gap in our knowledge of ovarian immune regulation. My 
recent investigations have demonstrated that these DNTs arise from peripheral CD8+ T cells that 
downregulate the CD8 coreceptor, adopting a unique transcriptional profile and acquiring suppressive 
functions. In models of autoimmune ovarian failure (AOF), DNTs are markedly reduced, correlating with 
ovarian dysfunction and infertility, while adoptive transfer of DNTs restores ovarian function and fertility by 
restraining pathogenic CD8+ T cell responses. Intriguingly, emerging observations indicate that DNTs also 
accumulate within ovarian tumors, suggesting a complex role in reproductive health by simultaneously 
modulating autoimmunity and potentially promoting local immune tolerance that could be co-opted by 
tumors. The central hypothesis of this project is that the reprogramming of peripheral CD8+ T cells into 
DNTs constitutes a critical immune checkpoint in the ovary, which can be harnessed to treat AOF and 
strategically modulated to enhance anti-tumor immunity. Specifically, this project will: (1) elucidate the 
molecular and transcriptional mechanisms driving the conversion of CD8+ T cells into regulatory DNTs 
within the ovarian microenvironment; (2) determine how DNTs suppress autoreactive T cells to maintain 
fertility in AOF models; (3) investigate how ovarian tumors exploit this pathway to establish local immune 
tolerance; (4) develop targeted strategies to enhance ONT-mediated tolerance in autoimmune conditions; 
and (5) explore engineering DNTs to restore CD8-associated cytotoxic programs as a novel approach

## Key facts

- **NIH application ID:** 11494461
- **Project number:** 4R00HD109370-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Enitome  Bafor
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** HD
- **Fiscal year:** 2026
- **Award amount:** $248,976
- **Award type:** 4N
- **Project period:** 2023-04-01T00:00:00 → 2029-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11494461

## Citation

> US National Institutes of Health, RePORTER application 11494461, Reprogramming Double Negative T Cells to Combat Autoimmune Ovarian Failure and Ovarian Tumors (4R00HD109370-02). Retrieved via AI Analytics 2026-06-27 from https://api.ai-analytics.org/grant/nih/11494461. Licensed CC0.

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