MDSCs are induced after experimental blunt chest trauma and subsequently alter antigen-specific T cell responses.

Severe blunt chest trauma (TxT) induces a strong inflammatory response with posttraumatic immune suppression pointing to an impaired adaptive immune response. Since CD11b+Gr-1+-expressing myeloid-derived suppressor cells (MDSCs) are induced after inflammation and suppress T cell responses, MDSC induction and their impact on T cell functions was analysed in an experimental TxT model. MDSCs were induced preferentially in the lung until 24 hours after TxT. Although MDSC numbers were only faintly increased in the spleen, splenic MDSCs isolated after TxT strongly inhibited alloantigen-induced T cell proliferation in vitro. Suppressive activity correlated with increased expression of arginase-1 and iNOS. MDSCs also prevented antigen-induced T cell expansion in vivo, since staphylococcus enterotoxin B (SEB)-induced proliferation of vß8+ T cells was impaired in TxT mice in the presence of CD11b+Gr-1+ cells. Surprisingly, MDSCs were not involved in shifting T cells into Th2 cells, characterized by the secretion of cytokines impairing cell-mediated immunity and promoting immunosuppression. Instead, the presence of CD11b+Gr-1+ cells was required for efficient IL-2, IFN-γ and TNFα production after antigenic stimulation, indicating, that elevation of MDSCs early after traumatic injuries might contribute to restrict the initial inflammatory response by alleviating T cell expansion, however, without impeding Th1 functions.

Role of hypoxia inducible factor-1α for interferon synthesis in mouse dendritic cells.

Dendritic cells (DCs) are an important link between innate and adaptive immunity. DCs get activated in inflamed tissues where oxygen tension is usually low, which requires the transcription factor hypoxia inducible factor (HIF)-1 for cellular adaptation. To investigate whether the HIF-1 transcriptional complex plays a pivotal role in the function of DCs, we compared the effects of exogenous inflammatory stimuli and hypoxia on HIF-1α in bone marrow-derived DCs from wild type and myeloid-specific HIF-1α knock-out mice. We showed that the Toll-like receptor ligands lipopolysaccharides and cytosine-phosphatidyl-guanines significantly induce HIF-1α mRNA and protein, leading to elevated HIF-1 target gene expression of vascular endothelial growth factor. In contrast, polyinosinic:polycytidylic acid did not show comparable effects. Furthermore the potential to up-regulate inflammatory cytokines critically influences DC function. Our data demonstrate that HIF-1α protein is needed for adequate production of interferon-α and -ß. In co-cultures of DCs and cytotoxic T cells, we observed that DCs lacking active HIF-1α protein induce significantly less CD278 and granzyme B mRNA in T cells. We conclude that HIF-1α plays a crucial role in DC interferon production and T cell activation, linking the innate and adaptive immune system.

The regulatory T-cell response during acute retroviral infection is locally defined and controls the magnitude and duration of the virus-specific cytotoxic T-cell response.

Cytotoxic CD8(+) T cells control acute viremia in many viral infections. However, most viruses that establish chronic infections evade destruction by CD8(+) T cells, and regulatory T cells (Treg) are thought to be involved in this immune evasion. We have infected transgenic mice, in which Treg can be selectively depleted, with Friend retrovirus (FV) to investigate the influence of Treg on pathogen-specific CD8(+) T-cell responses in vivo. We observed that Treg expansion during acute infection was locally defined to organs with high viral loads and massive activation of virus-specific effector CD8(+) T cells. Experimental ablation of Treg resulted in a significant increase of peak cytotoxic CD8(+) T-cell responses against FV. In addition, it prevented the development of functional exhaustion of CD8(+) T cells and significantly reduced FV loads in lymphatic organs. Surprisingly, despite the massive virus-specific CD8(+) T-cell response after temporary Treg depletion, no evidence of immunopathology was found. These results demonstrate the important role of Treg in controlling acute retrovirus-specific CD8(+) T-cell responses, and suggest that temporary manipulation of Treg might be a possible therapeutic approach in chronic infectious diseases.