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Unravelling gamma delta T cell emergence and responses in the uterus

Periodic Reporting for period 1 - UTERUS (Unravelling gamma delta T cell emergence and responses in the uterus)

Reporting period: 2018-03-01 to 2020-02-29

T cells are a central component of the immune system. Two main subsets -alpha beta and gamma delta (gd)- can be described, according to the composition of the cell membrane receptors they use to detect antigen. gd T cells usually constitute a small proportion of blood lymphocytes (1-5%), but are enriched at barrier sites, such as the skin and the intestine, where they reside in close contact with epithelial cells. Their location at key sites of infection and cellular transformation, together with their ability to detect tissue perturbations, are ideal properties for a natural immunosurveillance compartment. This has been highlighted recently by their identification as the single most significant human immune population correlating with a favourable cancer prognosis. Nonetheless, despite much effort on elucidating the mechanisms of T cell activation and the cells’ involvement in host protection, much of the biology of gd T cells remains obscure. To address this, it is important to consider how these specialised lymphocytes interact with specific host tissues.
This project sought to elucidate the biology of uterine gd T cells, one of the least understood populations of gd T cells. For example, their spatial and temporal location relative to the uterine epithelium and stroma are ill-defined. Moreover, there is little understanding of T cells more generally in the reproductive tract, a site highly vulnerable to infection and malignant transformation, and a common focus of medical intervention.
In this context the overarching goals for this project were:

1- To characterize and define the function of uterine gd T cells. In this aim, we determined the precise tissue localisation, dynamics and functional properties of uterine gd T cells.
2- To identify the endogenous and environmental mechanisms regulating uterine gd T cells. In this aim, we sought to identify and characterise candidate molecules that regulate the development and/or maintenance of uterine gd T cells, asking whether they act via generalisable mechanisms in common with skin and gut gd T cells, or whether they are unique. Additionally, we studied whether the microbiome regulates the development and/or function of uterine gd T cells, as has been claimed to be the case for some other gd T cell compartments.

Our data have generated the most comprehensive analysis to date of gd T cells in the murine uterus, highlighting their localisation within the uterine stroma and their population kinetics. We have also shown that the cells express a set of characteristic molecules, among which is the proinflammatory mediator IL-17A, which is associated with protection against fungal infections. Indeed, despite being dispensable for normal pregnancy, gd T cells played a critical role in protection of the female reproductive tract against Candida albicans infection.
This project has yielded the most comprehensive analysis to date of gd T cells in the murine uterus, and has highlighted the existence of a unique local T cell compartment. Consistent with earlier reports, most cells expressed an invariant T cell receptor, comprised of the Vg6 and Vg1 chains. The cells predominantly produced IL-17A, a pro-inflammatory mediator that has been associated with protection against pathogens and with the development of autoimmune disease. However, contrasting with earlier widely-cited reports uterine gd T cells were not obviously embedded in the epithelium. Rather, they resided in the uterine stroma, akin to similar gd cell populations at several other anatomical sites such as the dermis or intestinal lamina propria. In addition, the uterine gd T cell compartment was strikingly enriched in young mice and it expressed genes hitherto associated with the uterus, such as the progesterone receptor, suggesting that the cells adapt their gene expression to their tissue of residence. Furthermore, uterine gd T cells did not require microbes for their development and/or maintenance. While it is tempting to link their abundance in young animals to sexual maturation, none of our studies strongly implicated gd T cells in reproductive fitness. This notwithstanding, gd T cell deficiency severely impaired resistance to fungal infection in the female reproductive tract, partly through a reduced ability to recruit cells of the immune system responsible for engulfment and elimination of the pathogen.

Results from this project were presented as posters and oral presentations at various regional and international conferences, including the 8th international gd T cell conference in Bordeaux in 2018, the ThymE T cell and Thymus Biology conference in Israel in 2019, the Mucosal Immunology Conference in Australia in 2019 and the British Society for Immunology (BSI) annual conference in 2019. Furthermore, the data was presented in internal Crick and King’s College seminars, and as part of our weekly lab meeting which provided productive feedback for the project.

Our findings from this project were submitted for publication to Mucosal Immunology in October 2019, and received favourable reviews. All experiments requested by the reviewers were completed and a revised manuscript was resubmitted in April 2020. In addition, the initial UTERUS project has led to the initiation of two additional research projects, which we estimate will be ready for submission at the end of 2020/beginning of 2021. In addition to these research papers, in 2019, Dr. Monin co-authored a review article in Immunology titled “Immune responses in the human female reproductive tract”.

Furthermore, we were able to communicate our research objectives from the UTERUS project to a variety of audiences through participation in several outreach and teaching activities, which included a Genetic Engineering practical workshop organised by the public engagement team at the Crick; a Medicine at the Crick course organised by UCL; and an outreach activity to school children aged 4-5.
This project is benefitting the scientific community and society at different levels: (1) Contribution to science, innovation and generation of knowledge: this project has contributed valuable novel insights into the mechanisms regulating immunity and T cell biology in the female reproductive tract; (2) Contribution to public health and welfare: understanding the mechanisms underlying uterine immunity could aid in the development of therapies for reproductive system pathologies, including infection, cancer and reproductive failure; (3) Public engagement, promotion of the research profession and increasing scientific literacy; (4) One of the priorities of the European Research Area is to promote gender equality. The project focuses on a problem where gender disparities exist, namely regarding the higher incidence of sexually transmitted infections in women; (5) This project has contributed to one of the Europe 2020 targets, in increasing research mobility and cross-border cooperation. We believe that this has been achieved through the establishment and reinforcement of regional collaborations, secondments and presentations at conferences.
Graphical Summary of the UTERUS project objectives