T cells are necessary for development of PCOS reproductive symptoms in a letrozole-induced mouse model of PCOS

Ujagar, N.; Velez, L.; De Robles, G.; Nguyen, C.; Wiggins, K.; Kim, J.; Naidu, N.; Angulo, J. A.; Kaufmann, A. S.; Thackray, V. G.; Banaszewska, B.; Wysocka, E.; Duleba, A.; Seldin, M. M.; Nicholas, D. A.

doi:10.1101/2025.01.08.631835

bioRxiv · 10.1101/2025.01.08.631835

T cells are necessary for development of PCOS reproductive symptoms in a letrozole-induced mouse model of PCOS

Ujagar, N.·Velez, L.·De Robles, G.·Nguyen, C.·Wiggins, K.·Kim, J.·Naidu, N.·Angulo, J. A.·Kaufmann, A. S.·Thackray, V. G.·Banaszewska, B.·Wysocka, E.·Duleba, A.·Seldin, M. M.·Nicholas, D. A.

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Abstract

Polycystic ovary syndrome (PMOS) is a complex reproductive disorder with clear genetic susceptibilities that impact the heterogeneous clinical presentation of symptoms and severity through unknown mechanisms. Chronic inflammation is linked to PMOS, but a clear cause-and-effect relationship between immune mediators and PMOS phenotypes has yet to be demonstrated. This study employed a comprehensive systems immunology approach, utilizing a letrozole-induced PMOS mouse model to identify changes in inflammatory factors associated with PMOS symptoms. By analyzing immune cells and secreted cytokines from 22 different mouse strains, we identified T cells and TNF-{beta} as associated with PMOS-like phenotypes, regardless of genetic background. We used a knockout of TCR to show that functional T cells are necessary for development of pathologically elevated luteinizing hormone (LH) in letrozole-treated female mice. In women with PMOS, we observed elevated TNF-{beta} transcripts in immune cells from women with PMOS. Finally, we demonstrate that TNF-{beta} increased Lhb mRNA in a female mouse gonadotrope-derived cell line, suggesting that TNF-{beta} may directly modulate gonadotrope gene expression and may contribute to elevated LH in PMOS-like conditions. These findings support a requirement for functional {beta} T cells in LET-induced LH elevation in a PMOS-like mouse model and identify TNF-{beta} as a candidate immune mediator for further investigation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/631835v2_ufig1.gif" ALT="Figure 1"> View larger version (90K): org.highwire.dtl.DTLVardef@14dcf2aorg.highwire.dtl.DTLVardef@15bdc67org.highwire.dtl.DTLVardef@1e2f718org.highwire.dtl.DTLVardef@1cc5c16_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryFunctional {beta} T cells are linked to LET-induced LH elevation in a PMOS-like mouse model, uncovering candidate immune mechanisms for further study.

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Ujagar, N., Velez, L., De Robles, G., Nguyen, C., Wiggins, K., Kim, J., Naidu, N., Angulo, J. A., Kaufmann, A. S., Thackray, V. G., Banaszewska, B., Wysocka, E., Duleba, A., Seldin, M. M., Nicholas, D. A.. 2025-01-13. T cells are necessary for development of PCOS reproductive symptoms in a letrozole-induced mouse model of PCOS. https://doi.org/10.1101/2025.01.08.631835

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