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The underlying mechanisms by which prior immunity to dengue virus (DENV) affords cross-protection against the related flavivirus Zika virus (ZIKV) are poorly understood. Here, we examine the ability of DENV/ZIKV-cross-reactive CD4 + T cells to protect against versus exacerbate ZIKV infection by using a histocompatibility leukocyte antigen (HLA)-DRB1 ∗ 0101 transgenic, interferon α/β receptor-deficient mouse model that supports robust DENV and ZIKV replication. By mapping the HLA-DRB1 ∗ 0101-restricted T cell response, we identify DENV/ZIKV-cross-reactive CD4 + T cell epitopes that stimulate interferon gamma (IFNγ) and/or tumor necrosis factor (TNF) production. Vaccination of naive HLA-DRB1 ∗ 0101 transgenic mice with these peptides induces a CD4 + T cell response sufficient to reduce tissue viral burden following ZIKV infection. Notably, this protective response requires IFNγ and/or TNF secretion but not anti-ZIKV immunoglobulin G (IgG) production. Thus, DENV/ZIKV-cross-reactive CD4 + T cells producing canonical Th1 cytokines can suppress ZIKV replication in an antibody-independent manner. These results may have important implications for increasing the efficacy and safety of DENV/ZIKV vaccines and for developing pan-flavivirus vaccines., Competing Interests: Declaration of Interests The La Jolla Institute for Immunology has a pending USA patent application, 16/537,447, covering methods and compositions utilizing the epitopes described in this manuscript for the treatment and prevention of flaviviruses, with S.S. listed as the inventor., (Published by Elsevier Inc.)

T cell exhaustion is a state of hyporesponsiveness that develops during many chronic infections and cancer. Neutralization of inhibitory receptors, or "checkpoint blockade," can reverse T cell exhaustion and lead to beneficial prognoses in experimental and clinical settings. Whether checkpoint blockade can resolve lethal acute infections is less understood but may be beneficial in vaccination protocols that fail to elicit sterilizing immunity. Since a fully protective vaccine for any human parasite has yet to be developed, we explored the efficacy of checkpoint inhibitors in a mouse model of Toxoplasma gondii reinfection. Mice chronically infected with an avirulent type III strain survive reinfection with the type I RH strain but not the MAS, GUY-DOS, and GT1 parasite strains. We report here that mouse susceptibility to secondary infection correlates with the initial parasite burden and that protection against the RH strain is dependent on CD8 but not CD4 T cells in this model. When given a lethal secondary infection, CD8 and CD4 T cells upregulate several coinhibitory receptors, including PD-1, TIM-3, 4-1bb, and CTLA-4. Moreover, the gamma interferon (IFN-γ) response of CD8 but not CD4 T cells is significantly reduced during secondary infection with virulent strains, suggesting that checkpoint blockade may reduce disease severity. However, single and combination therapies targeting TIM-3, CTLA-4, and/or PD-L1 failed to reverse susceptibility to secondary infection. These results suggest that additional host responses, which are refractory to checkpoint blockade, are likely required for immunity to this pathogen., (Copyright © 2018 American Society for Microbiology.)