[R00] Reprogramming Double Negative T Cells to Combat Autoimmune Ovarian Failure and Ovarian Tumors
Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Scadenza: 2029-03-31
Importo max: 248.976 EUR
Paese: US
Descrizione
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 to
overcome ovarian tumor immune barriers. These studies will reveal a previously unrecognized pathway of
peripheral T cell reprogramming with important implications for reproductive immunology. They will also
lay the groundwork for innovative immunotherapeutic strategies that leverage or redirect DNT functions to
restore ovarian health and improve outcomes in ovarian cancer, addressing critical unmet needs in
women's health.
Istituzione: UNIVERSITY OF FLORIDA
PI: Enitome Bafor
Progetto: 4R00HD109370-02
Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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