br Results br Discussion CD T cells are important for

Results
Discussion CD8 T α-mangostin are important for immune control of many viral infections (Ehtisham et al., 1993, Kagi et al., 1994, Mullbacher et al., 1999, Walsh et al., 1994). CD8 T cells are essential for efficient clearance of MAV-1 from the lungs and for airway inflammation during acute infection (Molloy et al., 2017). Effects of CD8 T cells on MAV-1 clearance and MAV-1-induced airway inflammation are independent of the CD8 T cell effectors IFN-γ and Pfn (McCarthy et al., 2015b, Molloy et al., 2017). In this study, we tested the hypothesis that those contributions of CD8 T cells to MAV-1 pathogenesis were mediated by Fas/FasL interactions. Our results indicate that CD8 T cell clearance of virus from the lungs of infected mice did not depend on Fas/FasL interactions. However, proinflammatory effects of CD8 T cells in the airways of MAV-1-infected mice were decreased in lpr mice, indicating that Fas/FasL interactions made essential contributions to those effects. Our results highlight a distinction between effector mechanisms that mediate the antiviral and proinflammatory effects of CD8 T cells during MAV-1 infection. Fas contributes to immune control of a variety of viruses, such as influenza (Topham et al., 1997), herpes simplex virus type 1 (Johnson et al., 2008) and type 2 (Dobbs et al., 2005, Ishikawa et al., 2009), West Nile virus (Shrestha and Diamond, 2007), and mouse hepatitis virus (Parra et al., 2000). Likewise, Fas deficiency impairs clearance of E1-deleted, replication-deficient HAdV vectors from the livers of mice following intravenous administration (Abougergi et al., 2005, Chirmule et al., 1999, Kafrouni et al., 2003). However, in this study we demonstrate that Fas deficiency did not affect control of MAV-1 replication, just as deficiency of IFN-γ or Pfn had minimal effect on MAV-1 replication or clearance of virus from the lungs (McCarthy et al., 2015b, Molloy et al., 2017). Overlapping activity of multiple CD8 T cell effectors appears to be sufficient to mitigate the effects of isolated Fas deficiency. This type of functional redundancy has been demonstrated in other models. For instance, Pfn and Fas exert redundant effects in the control of influenza replication (Topham et al., 1997), as do IFN-γ and Pfn for murine gammaherpesvirus 68 (Tsai et al., 2011). Similarly, Fas deficiency has no effect on control of other types of viral infections, including lymphocytic choriomeningitis virus, vaccinia virus, vesicular stomatitis virus, and Semliki Forest virus (Kagi et al., 1995). TRAIL may also serve as an important antiviral CD8 T cell effector mechanism during MAV-1 infection, as has been described for influenza (Brincks et al., 2008). TRAIL expression was similar in the lungs of B6 and lpr mice infected with MAV-1, supporting the possibility that its activity could have compensated for Fas deficiency in this study. TNF-α produced by CD8 T cells and other cell types induces diverse cellular responses, including apoptosis as well as the regulation of many innate and acquired immune responses (Rahman and McFadden, 2006). TNF-α inhibits replication of viruses such as influenza and herpes simplex virus (Mestan et al., 1986, Seo and Webster, 2002). In mouse models, TNF-α deficiency or blockade increase HAdV-based vector transgene delivery and delay clearance of HAdV-based vectors (Abougergi et al., 2005, Benihoud et al., 2007, Kafrouni et al., 2003, Minter et al., 2000). TNF-α expression increases in the lungs and airways during acute MAV-1 infection (McCarthy et al., 2013, Molloy et al., 2017). The results from the present study indicate that MAV-1-induced TNF-α production is decreased in the absence of Fas expression, similar to decreased TNF-α production that we previously observed in CD8 T cell-deficient mice infected with MAV-1 (Molloy et al., 2017). However, even the reduced levels of TNF-α produced by CD8 T cells or other types of cells in lpr mice may have been sufficient for CD8 T cell-mediated apoptotic killing of infected cells, particularly in conjunction with other intact CD8 T cell effector mechanisms such as TRAIL and Pfn.