Supplementary MaterialsFigure S1: PD-L1?/? PDL2?/? dual knockout show a similar sensitivity to IAV as wild type BALB/c. mice into iNKT cell deficient mice recapitulated these findings. Interestingly, in our transfer system PD-L1?/?-derived iNKT cells produced high levels of interferon-gamma whereas PD-L2?/?-derived iNKT cells produced high amounts of interleukin-4 and 13 suggesting a role for these cytokines in sensitivity to influenza. We identified that PD-L1 negatively regulates the frequency of iNKT cell subsets in the lungs of IAV infected mice. Altogether, these results demonstrate that lack of PD-L1 expression by iNKT cells reduces the sensitivity to IAV and that the presence of PD-L2 is important for dampening the deleterious inflammatory responses after IAV infection. Our findings potentially have clinical implications for developing new therapies for influenza. Introduction Influenza A virus (IAV) infections AR7 represent a major public health threat, particularly in the case of children, the elderly and those with underlying diseases, all of whom are at an increased risk for disease complications and death following IAV infection , . Seasonal outbreaks alone cause an estimated 200,000 hospitalizations and over 30,000 deaths annually in the United States . Immune system plays an important role in the resolution of IAV infection. Both mucosal and systemic immunity play important roles in the elimination of infection with IAV , , . Accumulating evidence within the last couple of years suggests a significant role for regular Compact disc4+ and Compact disc8+ T cells within the control and clearance from the IAV , , . Nevertheless, lately, a fresh T cell human population fairly, invariant organic killer T (iNKT) cells, have already been reported to do something not merely as innate lymphocytes but additionally as regulators of adaptive immune system reactions , . iNKT MLL3 cells have already been suggested to try out critical tasks in an array of immune system responses by performing inside a pro-inflammatory or anti-inflammatory way , . They’re a specific subset of T lymphocytes expressing markers from the NK cell lineage and an invariant T cell receptor (TCR) . As opposed to regular T cells, iNKT cells understand personal and exogenous lipid antigens shown from the MHC course I-like molecule Compact disc1d , . Upon lipid reputation through their TCR, iNKT cells secrete a variety of cytokines with opposing results on immune system responses, which donate to the activation of NK, B and T cells, and dendritic cells (DCs) . This practical real estate establishes iNKT cells as innate immune system effector cells in addition to regulators of adaptive immune system responses. Numerous research show that, upon activation, iNKT cells either suppress or improve immune-mediated reactions during inflammation, tumor, autoimmune illnesses and disease , , , . There’s evidence indicating that iNKT cell AR7 responses to viral infection require interaction of iNKT cells with DCs where co-stimulatory interactions may play an important role in determining the outcome of the response. The PD-1: PD-1 ligand co-stimulatory interaction is a recently characterized signaling pathways within the B7: CD28 superfamily. This co-stimulation consists of the PD-1 AR7 receptor and its two ligands PD-L1 (B7-H1) and PD-L2 (B7-DC). PD-L1 is expressed in a wide variety of tissues and by a number of different cell types including T cells, NK T cells and DCs , , , , and its expression is up-regulated by IFN- , . The expression of PD-L2 is much more restricted and appears to be limited to a subset of bone marrow-derived cells, including DCs and macrophages , . PD-1 is an inhibitory co-receptor that is expressed on T, iNKT and B cells after activation that delivers an inhibitory signal upon recognition of either of its ligands. Cytokines such as for example AR7 IL-4 and IFN- which are produced after T cell activation raise the.