*Purpose: Estrogen signaling is a critical component of mammalian homeostasis, acting through a complex and interconnected system of hormone synthesis pathways and receptor signaling cascades. Estrogen signaling is thought to play a role in nearly every cell type throughout the body, including cells of the immune system. However, the interactions and functions of estrogen signaling within the immune system have yet to be elucidated.

*Methods: We investigated the roles of estrogen receptor-alpha (ER-a) and estrogen receptor-beta (ER-b) in host T cells by undertaking their conditional deletion in adult mice, using floxed genes and tamoxifen-inducible Cre.

*Results: In the absence of ER-b, secondary lymphoid organs had increased proportions of CD4+ cells (ranging from 15-33%; p<0.05). Ratios of T effectors to T regulatory cells (Tregs), and follicular T effectors (Tfh) to follicular Tregs (Tfreg) were drastically increased within the spleens (48% increase of Tfh:Tfreg; p=0.0029), superficial lymph nodes (sLNs) (29% with p=0.0049 and 68% with p<0.0001, respectively), and mesenteric lymph nodes (mLNs) (26% with p=0.04 and 42% with p=0.0002, respectively). Germinal Center B cell proportions were increased in both lymph node types (sLNs by 80% with p=0.046; mLNs by 30% with p=0.049). Specifically in the mLNs, ER-b KO resulted in significantly higher proportions of follicular B cells (54% with p<0.0001), in addition to follicular type I and type II cells (53% with p<0.0001 and 63% with p=0.0001, respectively). ER-b KO mice also had decreased proportions of Tregs and Tfregs most prominently in the mLNs (37% with p<0.0001 and 60% with p=0.0014, respectively). While ER-a KO mice had fewer and less pronounced differences in immune cell proportions compared to WT, notably there were significantly less Tregs (31% with p=0.0007) in mLNs and their Tregs had decreased suppressive function in vitro.

*Conclusions: These data show that in the absence of estrogen signaling via ER-a or ER-b, cells within secondary lymphoid organs display inflammatory phenotypes, especially within the mLNs. In addition, these data suggest a potential role for estrogen signaling in influencing a tolerogenic immune environment suitable for transplantation. We are now undertaking studies to assess the effects of ER-a and ER-b deletion on allograft survival.

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