Developmental trajectory and function of Th10 cells in IBD

• Applicants: Professor Dr. Nicola Gagliani, Ph.D.; Professor Dr. Samuel Huber
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513484298

IBD is a devastating disease, and patients experience sever pain and thus severe limitations in their daily life. New therapies have been become available in the last years. Yet only about half of the patients achieve remission of the disease (therapeutic ceiling), up to 40% loss efficacy over time and only very few patients develop a status of tolerance allowing them to withdraw the medication. Finally, IBD incidence is increasing especially in industrialized countries. Considering all this, there is an urgent need to better understand the molecular and cellular mechanisms promoting IBD. This knowledge will set the basis for future therapies able to “break the IBD therapy ceiling”. We and others have proposed that CD4+ T cells, in particular Th1 and Th17 cells, play a crucial role in the IBD. The cytokines IL-12 and IL-23 promote the emergence and the pathogenicity of these cells. Accordingly, antibodies blocking these cytokines induce and maintain remission in a significant fraction of IBD patients. Yet, as reported above, current therapies induce remission in about half of the patients. The reason why part of the IBD patients do not respond is unclear. We propose that there are other, and so far, unrecognized CD4+ T-cell populations, which are not targeted by the current therapies and contribute to intestinal inflammation. In the first funding period we found unexpectedly that IL-10-producing Foxp3- CD4+ T cells include also a pro-inflammatory subpopulation, which are referred to as Th10 cells. Indeed, preliminary data show that Th10 cells are enriched in IBD patients and have the potential to induce colitis in a mouse IBD model. Based on this we hypothesise that Th10 cells drive IBD. We will test this hypothesis by analysing IBD patients before and after biological therapies. Furthermore, we will use established and new mouse models to validate in vivo the developmental trajectory, metabolism, and pathogenic potential of Th10 cells. Working on this aspect, it will allow us to discoverer new players explaining the pathogenicity of IBD and, as a long-term goal, also new targets for future IBD therapies.

• DFG Programme: Research Grants