The regulatory role of natural progesterone in barrier immunity

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ABSTRACT: Progesterone (P4) is a key sex hormone governing the physiological changes of the menstrual cycle. We and others have shown that it also has anti-inflammatory effects on the immune system locally in the female reproductive tract (FRT), but the mechanisms are not well understood. There are also indications that its immune effects reach beyond the FRT and affect immunity systemically. P4’s effects are likely modified by the more pro-inflammatory effects of estradiol (E2). A detailed understanding of the mechanisms behind P4’s immune activities at local and systemic sites, and its interactions with E2, may contribute to women’s health by explaining sex-based and menstrual cycle-related fluctuations in inflammatory diseases. Some inflammatory diseases fluctuate during the menstrual cycle, suggesting that P4 has systemic immune effects. For example, asthma and inflammatory bowel disease worsen in the P4-low follicular phase, while rheumatoid arthritis often improves in the P4-dominant luteal phase. On the other hand, P4-induced immunosuppression could limit the response to vaccination or resistance to infection. P4 surges during the luteal phase of the menstrual cycle, reaching >40 times above follicular phase levels. Our data show a clear immunological difference in the FRT between the phases: luteal inhibition of macrophage- tropic chemokines by P4. Monocytes/macrophages and dendritic cells (DC) are antigen-presenting cells (APC), which provide key signals for the localization and survival of resident memory T cells (TRM). We propose complementary human and mouse studies: (1) a human cohort with studies at the APC level, probing their connections to TRM in the FRT and other barrier sites and (2) mouse experiments to corroborate P4’s immunological properties in combination with E2 and to test the hypothesis that vaginal CCL2/CCL4 administration partially reverses P4-induced immune suppression. In Aim 1, we will recruit a clinical cohort to study the effects of the P4-dominant luteal phase in humans on APC and TRM activation and function in the FRT, the gastrointestinal tract, the upper respiratory tract, the skin, and the blood. We will use MSD-based immune factor profiling of secretions and flow cytometry and single cell RNA sequencing of mucosal cells to address three hypotheses: (1) inhibition of APC-tropic chemokine production is a hallmark of barrier site immunosuppression during the luteal phase; (2) mucosal APCs are fewer or less inflammatory during the luteal than the follicular phase; and (3) the APC and cytokine changes during the luteal phase associate with lower number and/or activation status of TRM. In Aim 2, we will use mouse models to establish a causal link between P4 treatment, chemokine production, and APC & TRM frequencies and activation state. We will address two hypotheses: (1) P4 inhibits production of CCL2 and CCL4 in major barrier tissues, reducing APC and TRM frequencies and/or functional potential; and (2) vaginal CCL2/4 administration prevents P4-induced suppression of APC and TRM.