Let's be adaptable: Tissue T cell adaptation in homeostasis and inflammation

Abstract

Chronic inflammatory disorders such as juvenile idiopathic arthritis and Crohn’s disease are characterized by a relapsing-remitting pattern of inflammation. Many therapeutic options are aimed at suppressing the immune system. We do not know, however, how (regulatory) T cells are programmed and adapt during inflammation, and therefore what we can best target therapeutically. In this thesis we have investigated how regulatory T cells, which suppress the immune system, adapt to the environment of residence. We show that these cells acquire an overarching activated and highly suppressive profile irrespective of the type of inflammation, e.g. auto-inflammation in juvenile idiopathic arthritis or inflammation in cancer. The local environment further refines the profile with environment-specific markers for optimal local functioning. Moreover, we have studied how T cells adapt to the epithelium and lamina propria of the intestine. The profile of these cells completely differs even though these environments are separated by a basement membrane of only 7 µm. T cells in the epithelium have the ability to quickly react but also express many regulatory markers translating to an ‘activated-yet-resting’ profile. T cells in the lamina propria have an activated profile with cytokine and granzyme production to quickly react to stimuli. During inflammation in Crohn’s disease the cells in the epithelial layer acquire a profile similar to cells in the lamina propria, which could potentially prolong inflammation. Concluding, the location of a T cell is the main determinant of its profile. This thesis broadens our understanding of local programming and adaptation of the immune system.