HLA transgenic mice are widely used to model the human

HLA-transgenic mice are widely used to model the human T cell response in mice. We focused the present study on the HLA B*0702 allele, which is associated with strong T cell response in terms of magnitude and breath (Weiskopf et al., 2013), thereby allowing us to test the role of multiple cross-reactive epitopes using our HLA B*0702-transgenic IFN-α/βR−/− mouse model of DENV2 infection. Studies with DENV-exposed human PBMC have shown that serotype cross-reactive T ARQ 621 Supplier can be preferentially activated and can exhibit an altered phenotype in terms of cytokine production, degranulation, and avidity (Mangada and Rothman, 2005; Mongkolsapaya et al., 2003; Mongkolsapaya et al., 2006). In particular, Rothman and colleagues reported a lower affinity of CD8 T cells for the sequence from another serotype during secondary infection and preferential cytokine production in favor of TNFα by cross-reactive CD8 T cells (Bashyam et al., 2006). Screaton and colleagues similarly reported activation of cross-reactive CD8 T cells with low avidity in DHF/DSS patients (Mongkolsapaya et al., 2003). Based on these findings, cross-reactive T cells have been hypothesized to play a pathogenic role during DENV infection. Our results, however, show that cross-reactive T cells do not appear to exhibit an altered cytokine profile and that cross-reactive T cells can decrease viral burden in tissues despite having lower magnitude and avidity than serotype-specific T cells. Our findings are consistent with an increasing number of new studies implicating a protective role for T cells during DENV infection in humans. In addition to our studies revealing an association between HLA-linked T cell responses and disease susceptibility (Weiskopf et al., 2013; Weiskopf et al., 2015b), an earlier study by a different group observed that the breadth and magnitude of the CD8 T cell response during secondary DENV infection was not significantly associated with disease severity (Simmons et al., 2005). Most recently, another group reported that the expansion of effector memory CD8 T cells during acute DENV infection correlated with reduced viremia (de Matos et al., 2015). Using H-2b mice (i.e. non HLA-transgenic) lacking IFN-α/β receptor alone or both IFN-α/β and γ receptors, we have previously demonstrated that CD8 T cells can play a critical role in protection against DENV in the context of primary infection (Yauch et al., 2009; Prestwood et al., 2012), vaccination (Zellweger et al., 2013), heterotypic secondary infection (Zellweger et al., 2015), and ADE (Zellweger et al., 2014). The present study with HLA transgenic mice highlights the role of serotype-specific and cross-reactive CD8 T cells in protection against DENV infection in the context of epitopes that are recognized by humans. Collectively, our studies with mouse models and new studies supporting a protective role for CD8 T cells against DENV infection in individuals from endemic countries imply that a dengue vaccine should elicit a robust, long-lasting CD8 T cell response. Based on the present results, this optimal CD8 T cell response should ideally include a combination of each of the four DENV serotype-specific, conserved (i.e. identical in more than one serotype), and cross-reactive CD8 T cells that are polyfunctional. However based on the present study, we cannot reject the possibility that cross-reactive T cells are pathogenic at late stages of DHF/DSS development. For instance, pathogenic T cells may be a consequence of DHF/DSS rather than a cause. In this scenario, cross-reactive T cells are protective in most secondary infection cases but some unknown factors induces an irregularity in the environment that switch the function of T cells from protective to pathogenic in DHF/DSS patients. Studies investigating the role of cross-reactive CD8 T cells in the context of severe vs. mild disease using IFN-α/βR−/− mice that are transgenic for particular alleles associated with strong vs. weak T cell responses may reveal the potentially pathogenic role of cross-reactive T cells during DENV infection.