The authors were interested in the adaptive immune correlates of protection against Zika virus (ZIKV) disease. They particularly examined the role of CD4+ T cells in protection against neuroinvasive ZIKV disease. The authors found an important role for CD4+ T cells in protection, as when CD4+ T cells were absent in mice they suffer from more severe neurological sequelae with significant increases in viral titres in the CNS. When CD4+ T cells from ZIKV immune mice were transferred to type I interferon receptor deficient animals they were found to be protected from a lethal challenge, suggesting that this CD4+ T cell response is necessary and sufficient for control of ZIKV disease. The authors then used a peptide library that spans the complete ZIKV polyprotein to identify both ZIKV-encoded CD4+ T cell epitopes that initiate immune responses and ZIKV-specific CD4+ T cell receptors that recognise these epitopes. In the ZIKV antigen-specific TCRβ repertoire the authors noted a high degree of diversity, both in response to a single epitope and among different mice responding to a CD4+ T cell epitope. Therefore there is a novel role for polyfunctional and polyclonal CD4+ T cells in providing protection against ZIKV infection and any vaccines developed against ZIKV need to elicit robust CD4+ T cell responses in order to prevent ZIKV neuroinvasion and limit replication within the CNS.
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