CD4+ T cell response against food antigens in intestinal disease
One particularly important task of the immune system is to distinguish harmless antigens, such as those found in food, from dangerous antigens. This process is known as oral tolerance and works very efficiently in healthy individuals, but it can also be disrupted, leading to food intolerances, allergies, celiac disease, or mucosal inflammation in patients with IBD. The adaptive immune system, in particular antigen-specific CD4+ T cells, are thought to play a key role in this process, but the exact mechanisms leading to the development and maintenance, as well as the failure, of oral tolerance are still not fully understood. T cells that recognize one particular antigen are very rare due to the high receptor diversity of the T cell repertoire, which has made a detailed characterization of food-reactive T cells difficult to date. In this thesis, a highly sensitive and specific technology, the Antigen-Reactive T Cell Enrichment (ARTE) method was used to directly identify and characterize CD4+ memory T cells specific for food antigens in human samples. Comparison of food-reactive CD4+ T cell responses, especially against wheat, between healthy donors and patients with IBD, identified novel mechanisms of how oral tolerance can be broken. This work demonstrated that CD4+ T cells specific for foods are present in healthy donors, but that these differ in terms of their frequency and functional characterization depending on the type of food. This suggests that different mechanisms may contribute to the maintenance of oral tolerance. In addition, single-cell sequencing was used to characterize wheat-reactive T cells in patients with IBD and healthy donors at high resolution. Interestingly, in Crohn's disease patients an immunological subgroup emerged whose wheat-reactive T cells exhibited a pro-inflammatory, cytotoxic Th1 phenotype. These wheat-reactive cytotoxic Th1 cells were also cross-reactive to commensal microbes, which are believed to be a direct trigger for altered CD4+ T cell responses in patients with Crohn's disease. This suggests that in this subgroup of CD patients, a network of cross-reactivities between commensal microbiota, wheat, and other cereals leads to chronic activation of cytotoxic CD4+ T cells and their selective expansion.
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