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

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.