Innate lymphocytes in the female genital tract and their role in chlamydial infection

• Applicant: Professor Dr. Georg Häcker
• Subject Area: Immunology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320257215

The role of populations of innate lymphocytes (ILCs) has been investigated at a number of mucosal surfaces and some of their activities have been worked out, for instance in the intestine and the respiratory tract. The female genital tract also is a substantial mucosal surface that serves as the site of initial infection for a number of pathogens. Very little is known about ILC-populations in the lower and higher genital tract in women and female mice, and almost no functional information is available. Chlamydia trachomatis is the most frequent bacterial agent of sexually transmitted disease with a high prevalence in young women. C. trachomatis initially infects the genital tract through the cervical epithelium but can ascend into the uterus and the oviducts and cause pelvic inflammatory disease, leading to substantial tissue damage. In a mouse model, chlamydial infection is during the first week characterised by a neutrophilic infiltrate, which is later replaced by T cells. We used the mouse model of intravaginal infection with C. muridarum in reporter mice that permit the definition of classical (c)NKs, ILC1s and ILC3s. We found that cNKs are the largest population of ILCs at steady state in the genital tract, with smaller populations of ILC1s and ILC3s. Four days after infection with C. muridarum we observed a massive expansion of ILC1s and smaller, still substantial, expansions of cNKs and ILC3s. Substantial production of IFN-gamma from cNKs and of TNF from ILC1s was observed at that point. We hypothesise that this strong response early in the infection contributes to the shape of the immune response to Chlamydia and to development and outcome of the infection. In this project we will test this hypothesis by pursuing three specific goals. First, we will characterize the subpopulations of ILCs in the genital tract in terms of cellular composition and characteristics, activity and effector capacity. Secondly, we will analyse the upstream signals activating these ILCs during chlamydial infection. We will establish which populations of cells in the genital tract produce key cytokines during chlamydial infection (IL-12, -15 and -18), and which effects these cytokines have on ILC expansion and activity. Thirdly, using genetic models of ILC-depletion we will endeavour to work out the importance of ILCs and ILC-subpopulations for chlamydial replication and anti-chlamydial defence, for the shape of the myeloid and lymphocytic immune response, the CD4 memory response and for the extent of tissue damage. We believe that the results of this project will permit insight not only into the ways how ILCs contribute to the response to an important mucosal pathogen but also will provide information on the organization of the early immune response at this relevant site of infection.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1937: Innate Lymphoid Cells