CD4+T and CD8+T Cells in Uterus Exhibit Both Selective Dysfunction and Residency Signatures.

Unlike T cells in other tissues, uterine T cells must balance strong immune defense against pathogens with tolerance to semiallogeneic fetus. Our previous study fully elucidated the characteristics of γδT cells in nonpregnant uterus and the mechanism modulated by estrogen. However, comprehensive knowledge of the immunological properties of αßT (including CD4+T cells and CD8+T) cells in nonpregnancy uterus has not been acquired. In this study, we fully compared the immunological properties of αßT cells between uterus and blood using mouse and human sample. It showed that most of CD4+T cells and CD8+T cells in murine uterus and human endometrium were tissue resident memory T cells which highly expressed tissue residence markers CD69 and/or CD103. In addition, both CD4+T cells and CD8+T cells in uterus highly expressed inhibitory molecular PD-1 and cytokine IFN-γ. Uterine CD4+T cells highly expressed IL-17 and modulated by transcription factor pSTAT3. Moreover, we compared the similarities and differences between human and murine uterine T cell phenotype. Together, uterine CD4+T cells and CD8+ cells exhibited a unique mixed signature of T cell dysfunction, activation, and effector function which enabled them to balance strong immune defense against pathogens with tolerance to fetus. Our study fully elucidated the unique immunologic properties of uterine CD4+T and CD8+T cells and provided a base for further investigation of functions.

Tissue resident memory T cells are enriched and dysfunctional in effusion of patients with malignant tumor.

Purpose Most malignant effusion is secondary to metastases to the pleura or peritoneum and portend poor oncological outcomes. Malignant effusion has different tumor microenvironment from primary tumor, containing a variety of cytokines and immune cells and directly contacting with tumor cells. However, the characteristic of CD4+ T cells and CD8+ T cells in malignant effusion remains unclear. Methods Malignant effusion including peritoneal ascites and pleural fluid from thirty-five patients with malignant tumor were collected and compared with matched blood. A detailed characterization of CD4+ T cells and CD8+ T cells in malignant effusion were conducted using flow cytometry and multiple cytokines assay. Results The concentration of IL-6 in malignant effusion was significantly higher than in blood. A substantial portion of T cells in malignant effusion were CD69+ and/ or CD103+ Trm cells. Most CD4+T and CD8+T cells in malignant effusion were exhausted T cells which expressed lower levels of cytokines, cytotoxic molecules and markedly higher levels of inhibitory receptor PD-1 compared with in blood. Conclusion Our study is the first to identify the presence of Trm cells in malignant effusion and will lay the foundation for future research on anti-tumor immunity of Trm cells in malignant effusion.

Estrogen enhanced the expression of IL-17 by tissue-resident memory γδT cells from uterus via interferon regulatory factor 4.

Tissue-resident memory γδT cells at mucosal and epithelial sites play an important role for pathogen clearance, immunosurveillance, and participating in physiological processes. Different from other barrier sites, the immune cells in uterus face the protection against infections and tolerate an allogeneic fetus during a successful pregnancy. In the previous study, we found that tissue-resident memory γδT cells were enriched both in human and murine uterus and highly expressed IL-17 that promoted the invasion of trophocytes in vitro. In the current study, we found that γδT cells in uterus but not in blood or spleens expressed higher levels of estrogen receptors. The injection of estrogen into mice increased the proportion of γδT cells in uterus but not in spleens in vivo via CXCR3-CXCL10 chemokine axis. In addition, we found that estrogen enhanced the production of IL-17 but not IFN-γ in vivo and in vitro via interferon regulatory factor 4 but not RORγt and pSTAT3 at mRNA and protein levels. The analysis of cell transcriptome sequence further identified multiple differentially expressed genes between estrogen and control γδT cells. Our study demonstrated that estrogen directly act on γδT cells in uterus to enhance the production of IL-17 that might promote the invasion of trophocytes. Furthermore, our study might provide a new idea that estrogen increased the prevalence of autoimmune diseases in women by enhancing γδT cell-derived IL-17 production in uterus and uncover the critical pathological roles for estrogen in the development of autoimmune diseases.

Tissue Resident Memory γδT Cells in Murine Uterus Expressed High Levels of IL-17 Promoting the Invasion of Trophocytes.

γδT cells are non-conventional T cells and serve as the bridge for connecting the innate and adaptive immune systems. γδT cells form a substantial population at barrier sites and play an important role in the development of physiology, inflammation, autoimmune diseases and tumors. γδT cells not only distribute in the maternal-fetal interface during pregnancy but also in non-pregnant uterus. However, the phenotypes and functions of γδT cells in uterus were not clear. In the current study, we found that the percentages of γδT cells were significantly higher in uterus than peripheral blood and most of γδT cells in uterus were distributed in endometrium. Further studies indicated that the majority of γδT cells in uterus were memory cells with higher expression of CD44 and CD27 but lower expression of CD62L and CCR7 compared to those in blood. In addition, we found that γδT cells in uterus were tissue resident memory γδT cells expressing CD69, expressed high levels of CCR6, GranzymeB and CD107a. Moreover, γδT cells in uterus were activated and fully expressed transcription factor RORγt. After short time of activation, γδT cells in uterus significantly expressed high levels of IL-17 but not IFN-γ, which promotes the invasion of murine trophocytes. Taken together, our study will lay the foundation for future research on uterine γδT cells in pregnancy and autoimmune disease.