The role of cytotoxic CD161-expressing CD4+ T-cells in host defense during chronic inflammatory diseases of the gut.

• Applicant: Dr. Carl-Philipp Hackstein
• Subject Area: Gastroenterology ; Immunology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 403193363

The aim of the proposed project is to elucidate whether the CD161-expressing CD4+ T-cells from the gut can contribute to host defence against bacterial infections and if there is a connection between these cells and the pathology leading to or maintaining inflammatory bowel diseases (IBD). To that end, in an initial set of experiments it is planned to make a detailed characterization of these cells in terms of their TCR repertoire, their transcriptional program and their localization within the tissue.Preliminary experiments already revealed that a notable percentage of the CD161+CD4+ T-cells in the gut expresses the cytotoxic effector molecule Granzyme B upon activation. Hence, a central part is this project will be to analyse whether the CD161+CD4+ T-cells express other cytotoxic effector molecules like Perforin in addition to Granzyme B and whether they have the capacity to kill bacterially infected target cells directly.Scientific studies from different groups have linked gut bacteria to IBD in the past. For instance, it was shown that in patients suffering form Crohn’s disease, one of the two major forms of IBD, bacterial DNA is present in the granulomas characteristic for the disease and that the disease is associated with the presence of gut bacteria with an invasive phenotype. Interestingly, previous experiments from Professor Klenermans group revealed that CD161+CD4+ T-cells isolated from IBD patients expressed higher levels of inhibitory receptors and also displayed a defect in Granzyme B expression compared to healthy controls. In order to unravel if there is a connection between the CD161+CD4+ T-cells in the gut and the development or maintenance of IBD, it will be tested whether the severity of IBD correlated with the presence and functionality of these cells. To that end it is planned to isolate the CD161+CD4+ T-cells from patients in different stages of disease and determine their numbers, expression of inhibitory receptors and cytotoxic capacities.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. Paul Klenerman, Ph.D.