The immune system beyond protection: role of innate lymphoid cells in the regulation of the estrous cycle.

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Perturbations to steady state conditions are sensed by tissue resident immune cells, which elaborate the information received and respond by producing signals that shape the functions of other immune, as well as non-immune, cells. In recent years, it became clear that such perturbations are not only caused by harmful pathogens, rather immune cells play fundamental roles in many physiological processes not related to host protection. Major players in these scenarios are Innate Lymphoid Cells (ILCs) and myeloid cells, which populate the connective tissues underneath the epithelial layer of barrier organs and prime inflammatory responses through the production of different cytokines. Such signals then lead to the recruitment and activation of circulating lymphocytes, which mediate a response. In this research program, we propose to study immune cells in the female reproductive tract, a dynamic system which undergoes dramatic changes during the estrous cycle. Our working hypothesis is that immune cells are important regulators of the dynamic changes occurring during the estrous cycle. We will carry this project in collaboration with Dr. Vanderhyden, an expert in reproductive biology. In line with our research program, the short-term objectives of this Discovery Grant are: 1)To build an atlas of innate lymphoid cells in the female reproductive system: We will use single-cell RNA-sequencing (scRNA-seq) to characterize the immune composition of the female reproductive system. Ovaries, oviducts and uteri will be analyzed from mice at various stages of the estrous cycle and the periovulatory period. This analysis will reveal which immune cell populations and which pathways are modulated at the different stages of the estrous cycle. Immunohistochemistry, qPCR and flow cytometry will be employed to corroborate the scRNA-seq results. A particular emphasis will be given to innate lymphoid cells, which have been vastly overlooked in the female reproductive tract. 2)To determine if and how innate lymphoid cells regulate the progression through the estrous cycle: As we hypothesize that innate lymphoid cells are important coordinators of the dynamics of the estrous cycle, we will determine how experimental perturbation of this immunological compartment affects the estrous cycle. 3)To understand how endocrine signals regulate innate lymphoid cell functions during the estrous cycle: As innate lymphoid cells express receptors for neurotransmitters and hormones, we will study if they are directly regulated by the neuro-endocrine system. We will conduct functional in vivo and ex vivo experiments to determine which neuro endocrine signals regulate immune functions. This project will shed light on how immune cells regulate the estrous cycle and will represent a stepping stone to our broader goal of determining how the immune system contributes to the host physiology in the absence of a pathogenic challenge.