Lymphocyte function in inflammatory disorders of human endometrium and decidua

Endometriosis and polycystic ovary syndrome (PCOS) are major causes of female subfertility and infertility. Each is accompanied by chronic endometrial inflammation triggered and perpetuated by uncertain mechanisms. Potential roles for immune cells, specifically T and B lymphocytes, in endometrial inflammation are largely unexplored despite their being key orchestrators and mediators of tissue inflammation in many other non-uterine contexts. Furthermore, the antigen specificities of endometrial T and B cells are not well described, and whether self-antigen specific clones contribute to disorders with poor reproductive outcomes is unclear, despite evidence that endometriosis, in particular, may have an autoimmune component. These knowledge gaps represent major opportunities for improving reproductive outcomes for infertile patients with endometriosis and PCOS. Moreover, these disorders represent ideal models for investigating how immune dysregulation in the endometrium may contribute to infertility and subfertility more broadly. Accordingly, the goal of this project is to determine how T and B cells contribute to the pathogenesis of endometrial inflammation and, by extension, decidual inflammation, relevant to implantation failure and poor pregnancy outcomes. Herein, we propose to deeply characterize the frequencies, transcriptomes, proteomes, TCR/BCR repertoires, and antigen specificities of endometrial and decidual T and B cells across the menstrual cycle and in early pregnancy, respectively, in the context of healthy women (Aim 1) and those with endometriosis and PCOS (Aim 2). Particular emphasis will be placed on regulatory lymphocytes, which include conventional CD4+ regulatory T cells (Tregs), and cells from the CD8+ T cell and B cell lineages, since these cells are likely critical for ensuring a controlled inflammatory microenvironment optimal for implantation and successful pregnancy. Since the differentiation and function of these cells can be locally influenced by non-immune endometrial and decidual cells, such as stromal fibroblasts, Aim 3 will define the role of such cells in supporting suppressive lymphocyte differentiation and identify the key regulators involved in these processes. The proposal will also determine how endometriosis and PCOS alter the phenotypes of the NK cell lineage of lymphocytes, given the contribution of NK cells to important developmental events of early pregnancy. The Aims will be accomplished using archived and prospectively collected endometrial/decidual specimens from a total of 150 well-characterized subjects. Our central hypothesis is that different lymphocyte subsets with diverse roles in immunoregulation and microbial defense work together in a coordinated fashion to establish and maintain the appropriate endometrial and decidual environment for pregnancy success, and that these cells are altered and derailed by inflammatory disorders associated with poor reproductive outcomes. Completion of this study will reveal fundamental insights into lymphocyte contributions to tolerance and can reveal new targets for diagnostics and therapeutics to improve reproductive success.