One of the key features of the immune system of the intestine is its ability to induce tolerance towards “harmless” food antigens but profound immunity to pathogens and toxins. The objective of this project is to get a better understanding of how homeostatic chemokines and their receptor contribute to the functional organization of lymphoid structures of the intestine and how this affects the induction of tolerance and immunity.

The humoral immune response in the intestine is mainly mediated by IgA-secreting plasma cells. We were able to show that the chemokine receptor CCR9 controls the migration of mature plasma cells into the lamina propria of the small intestine. The amount of IgA- secreting plasma cells in CCR9-deficient animals is reduced by approximately 50%. Since we could show that, in addition to CCR9, lamina propria plasma cells express two further chemokine receptors, we will examine the role of these molecules in the CCR9-independent plasma-cell homing to the intestine.

It seems possible that one part of the plasma cells in the lamina propria might be derived from peritoneal B1-cells, which migrate from the peritoneum into the intestine. We were able to show, that CXCR5 and other chemokine receptors are essentially involved in the migration of the immune cells into the peritoneum. We will follow the hypothesis that homing defects into the peritoneal cavity will affect plasma cell homing to the intestine. Furthermore, the influence of the chemokine receptor CCR7 and CCR9 on the homing of T-cells into the gut will be characterized in detail by adoptive transfer experiments and a small intestine transplant model. These experiments aim to provide a better understanding for molecular mechanisms, which are adjusting the migration of plasma cells and active T-cells in the lamina propria.

In the context of a fundamental characterisation of intestinal immune cells, we found an as yet undocumented cell population with a phenotype that is similar to plasmacytoid dendritic cells. These cells make a possible contribution to local antiviral immunity. Due to the absense of this cell population in CCR9-mutants, we will examine their purpose by comparative infection experiments with CCR9-mutants and wild type mice. It seems that those chemokines that control homeostasis are also involved in the pathogenesis of autoimmune diseases and chronic inflammatory diseases. We therefore would like to address the role of CCR7 and CXCR5 in established colitis-models in the mouse.