Systems Genetics Cytokine Screen Identifies T cells as Necessary for Letrozole-Induced LH Elevation in a PMOS-like Mouse Model

Naveena S. Ujagar; Leandro M. Vélez; Christy M Nguyen; Kiara Dominique Wiggins; Gabriela De Robles; Zena D. Del Mundo; Siaje Gideon; Jessica Cassin; Joshua Kim; Nandini Naidu; Julio A Ayala Angulo; Benjamin Babaev; A Dingle; Margareta Danuta Pisarska; Ricardo Azziz; Jessica L. Chan; Rachel Ross; Alexander S. Kauffman; Varykina G. Thackray; Beata Banaszewska; Ewa Wysocka; Antoni J. Dulęba; Marcus Michael Seldin; Dequina Nicholas

doi:10.1101/2025.01.08.631835

ImmunologybioRxivJan 8, 2025

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Systems Genetics Cytokine Screen Identifies T cells as Necessary for Letrozole-Induced LH Elevation in a PMOS-like Mouse Model

Naveena S. Ujagar iD, Leandro M. Vélez iD, Christy M Nguyen iD, Kiara Dominique Wiggins iD, Gabriela De Robles, Zena D. Del Mundo iD, Siaje Gideon, Jessica Cassin iD, Joshua Kim, Nandini Naidu, Julio A Ayala Angulo, Benjamin Babaev iD, A Dingle, Margareta Danuta Pisarska iD, Ricardo Azziz iD, Jessica L. Chan iD, Rachel Ross iD, Alexander S. Kauffman iD, Varykina G. Thackray iD, Beata Banaszewska iD, Ewa Wysocka iD, Antoni J. Dulęba iD, Marcus Michael Seldin iD, Dequina Nicholas iD

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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.