Subproject A1

In this project we will test the hypothesis, that those antigen presenting cells (APC), which take up antigen from the gut and present it to T cells, regulate the decision between tolerance and immunity. The goal of our studies is to identify the molecular switches, which lead to tolerance via the induction of regulatory T cells. In the first period we have tried to define the APC more closely which take up antigen from the gut and present it to T cells. Taken together our results and those of others show that α_Eβ₇+ dendritic cells (DC) in the lamina propria (LP), which take up antigen in the gut mucosa and migrate into the mesenteric lymph nodes play a decisive role for the induction of the immune response as well as for oral tolerance.

Regarding potential molecular switches we could show that mRNA of the Notch ligand jagged1 is specifically expressed by DC in the mLN. Immunofluorescent staining revealed that jagged1 expression is restricted to the α_Eβ₇+ DC-subset which seems to be critically involved in induction of oral tolerance. Jagged1 has already been described with respect to induction of regulatory T cells. Our own functional analyses revealed that Notch modulates the T cell reaction via a) reduction of T cell activation by jagged1 b) the induction of the immunosuppressive cytokine IL-10 in Th1 cells which results in the conversion of these pro-inflammatory into protective anti-inflammatory T cells.

In the following period we will more close analyse the role of Notch for the immune reaction in the gut and in particular for the regulation of tolerance versus immunity. We will examine which role Notch-mediated signals play for the physiologic DC/T cell interaction. We plan to characterize Notch ligand expression on various APC subsets in the gut. By pharmacologic inhibition of Notch signals or by the use of mice with a DC specific k.o. of Notch ligands or alternatively a T cell specific deficiency of Notch signalling we will determine the role of Notch in immunogenic or tolerogenic immune reactions as well as during infections or in situations of chronic inflammations.

In addition we analyse the therapeutic potential of Notch-modulated Th1 cells in various in vivo models such as transfer colitis. We will try to clarify in which stages of disease these regulatory T cells can be protective and which effector molecules are involved. Furthermore we will continue our work to establish a detection system for specific peptide presentation by APC from the gut associated lymphoid tissues to be able to identify and better characterize the peptide presenting APC within the various immune reactions.