In sepsis the inflammatory phase is followed by an immune suppressive phase. In this project post-septic TNFR2-mediated immune suppressive mechanisms are being analyzed using genetically modified mice defective or transgenic for TNFR2. Splenic dendritic cells from TNFR2-deficient mice produced reduced levels of IL-12 while being highly activated for antigen presentation and skewing towards a Th2 cytokine profile. A low nitric oxide production capacity of macrophages of TNFR2-deficient mice was paralleled by increased arginase expression indicating immunosuppressive M2 characteristics similar to post-septic wild type macrophages. Taken together TNFR2-deficient mice seem to have an immune status comparable to wild type mice after sepsis. In addition, we showed that the development of Foxp3+ regulatory T cells (Treg) is TNF-dependent and identified TNFR2 as a good marker for functionally active Treg. Since TNFR2 can act in two different ways by either signaling after interaction with TNF or, alternatively, as a TNF inhibitor after being shed, experiments with bone-marrow chimeric mice will be used to determine in vivo the mechanistic function and physiological role of TNFR2. We are further interested to investigate whether and how the altered phenotype of TNFR2-deficient myeloid cells affects T cell functions and how they mediate the effects of TNFR2.
