Mapping and Protective Role of CD4+ T Cells against Zika Virus Infection in Mice Jing Sun, Guoxian Zhang, Jiaying Luo, Airu Zhu, Fang Li, Jingxian Zhao, Jincun Zhao State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University. Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that can cause severe disease in humans, including microcephaly in neonates and Guillain-Barré syndrome (GBS) in adults. To date, there is no effective vaccine against ZIKV infection licensed for human use. ZIKV-specific T cell responses are not well understood in animal model and human. In this study, the role of ZIKV specific CD4 T cells were investigated in both immunocompromised (IFNAR knockout) and immunocompetent wild type mice. Twelve ZIKV-specific CD4+ T cell epitopes were identified using a peptide library covering the whole polyprotein of ZIKV. CD4+ T cells in infected mice were polyfunctional and protective. Mice are more susceptible to ZIKV infection after CD4+ T cell depletion in vivo and showed higher viral load in serum and brains as compared to control group indicating that ZIKV-specific CD4+ T cells contribute to viral clearance. Vaccination of dominant CD4+ T cell epitopes protected mice from lethal ZIKV infection. Collectively, these results demonstrated that CD4+ T cells are protective against ZIKV infection in mice. This study will be useful for vaccine design against ZIKV.