Complement and regulatory T cells

The implication of regulatory T cells (Treg) in viral infection was first described for mice persistently infected with Friend virus (FV) but Tregs are supposed also to play a pathologic role in the establishment of chronic viral infections like HIV and HCV in humans. Our preliminary data indicates that the expansion of FV-induced Tregs is impaired in mice deficient for complement C3 suggesting that the complement system is critically involved in the generation of Treg responses during viral infections. This represents a novel research aspect of Treg biology. Therefore we will try to define key molecules involved in the interaction between complement and Tregs during retroviral infections. We will perform a detailed comparison of the activation and expansion of Tregs in FV infected wild-type mice and various mouse strains deficient for different complement components or complement receptors. In order to modify the polarization of T cell responses towards an effector vs. regulatory phenotype, we further will test the therapeutic potential of the interference with receptors during chronic infections using available complement receptor agonists and antagonists. Results of this project will increase our understanding on cellular and molecular mechanisms involved in regulatory T cell responses in chronic viral infections and may provide new treatment options.

Establishment of chronic viral infections might be a consequence of the induction and the expansion of regulatory T cells (Tregs). Growing evidence suggests that dendritic cells (DC) are involved in the expansion of Tregs, but the mechanisms of DC-Treg interaction are still elusive. Viruses that are opsonized with complement components have been shown to efficiently infect DC and thus might influence Treg responses. Using the Friend virus (FV) model, a mouse model for chronic retroviral infections, we found a delayed Treg expansion in knock-out mice deficient for the complement component C3. Surprisingly, this resulted only in a minor effect on anti-viral CD8 T cell responses or viral loads. However, we could demonstrate that virus particle opsonization (C3) was important for an efficient infection of DCs by the virus and both complement receptors CD11b and CD11c contributed to this effect. In the contrary to our original hypothesis, we were unable to experimentally demonstrate that FV-infected DCs preferentially expand Tregs. Overall, complement components do not seem to play a dominating role in the induction of Treg responses after virus infection, but clearly modulate anti-viral T cell responses by mechanisms that remain not fully understood.