Aberrant CD8+T cells drive reproductive dysfunction in female mice with elevated IFN-gamma levels

Author:

Bafor, Enitome E

Erwin-Cohen, Rebecca A

Martin, Toni

Baker, Clayton

Kimmel, Adrienne E

Duverger, Olivier

Fenimore, John M

Ramba, Meredith

Spindel, Thea

Hess, Megan M

Sanford, Michael

Lazarevic, Vanja

Benayoun, Bérénice A

Young, Howard A

Valencia, Julio C
Author Address

Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, United States., Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, United States., Molecular and Computational Biology Department, University of Southern California, Dornsife College of Letters, Arts and Sciences, Los Angeles, CA, United States., Craniofacial Anomalies and Regeneration Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States., Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States.,

Abstract:

Interferon-gamma (IFN-gamma) is pivotal in orchestrating immune responses during healthy pregnancy. However, its dysregulation, often due to autoimmunity, infections, or chronic inflammatory conditions, is implicated in adverse reproductive outcomes such as pregnancy failure or infertility. Additionally, the underlying immunological mechanisms remain elusive. Here, we explore the impact of systemic IFN-gamma elevation on cytotoxic T cell responses in female reproduction utilizing a systemic lupus-prone mouse model with impaired IFN-gamma degradation. Our findings reveal that heightened IFN-gamma levels triggered the infiltration of CD8+T cells in the pituitary gland and female reproductive tract (FRT), resulting in prolactin deficiency and subsequent infertility. Furthermore, we demonstrate that chronic IFN-gamma elevation increases effector memory CD8+T cells in the murine ovary and uterus. These insights broaden our understanding of the role of elevated IFN-gamma in female reproductive dysfunction and suggest CD8+T cells as potential immunotherapeutic targets in female reproductive disorders associated with chronic systemic IFN-gamma elevation. Copyright © 2024 Bafor, Erwin-Cohen, Martin, Baker, Kimmel, Duverger, Fenimore, Ramba, Spindel, Hess, Sanford, Lazarevic, Benayoun, Young and Valencia.

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