CD40-Signaling Induces Loss of Lamina Propria CD103+ Dendritic Cells, Abrogation of iTreg Induction and Fatal Colitis

Self/non-self discrimination is a hallmark of the immune system, where encounter with self-antigen induces tolerance, while the appropriate recognition of non-self antigen triggers immune reactions. A tight control of induction of immunity vs. tolerance is especially important at body surfaces such as the intestinal tract, where foreign, commensal-derived antigens must be tolerated. Dendritic cells (DCs) have key roles in this important equilibrium as they can induce both, immunity and tolerance, depending on their maturation status.

To further study signals in DCs that might contribute to tolerance in steady-state we focused on signaling via CD40. Although CD40-signaling in DCs is important for DC-licensing in combination with inflammatory signals, there is evidence that CD40-signaling alone induces incomplete maturation of DCs with regard to cytokine production. To investigate the influence of CD40 signals on DCs without the reported systemic, necroinflammatory effects induced by injected anti-CD40 mAb on CD40+ non-DCs, we generated transgenic mice, where selectively DCs receive a tonic CD40-stimulus.

DCs in spleens of these transgenic LMP/CD40-animals showed no signs of DC-activation with respect of costimulatory molecules and cytokine production. But all animals developed severe colitis, characterized by abundant IFNg+ and IFNg+IL17+ T cells in gut accompanied by highly elevated levels of proinflammatory cytokines. Disease development depended on presence of commensal bacteria as well as on B and T cells.