CD4+ T cells promote humoral immunity and viral control during Zika virus infection

Several Zika virus (ZIKV) vaccines designed to elicit protective antibody (Ab) responses are currently under rapid development, but the underlying mechanisms that control the magnitude and quality of the Ab response remain unclear. Here, we investigated the CD4(+) T cell response to primary intravenous and intravaginal infection with ZIKV. Using the LysMCre(+)Ifnar1(fl/fl) (myeloid type I IFN receptor-deficient) C57BL/6 mouse models, we identified six I-A(b)-restricted ZIKV epitopes that stimulated CD4(+) T cells with a predominantly cytotoxic Th1 phenotype in mice primed with ZIKV. Intravenous and intravaginal infection with ZIKV effectively induced follicular helper and regulatory CD4(+) T cells. Treatment of mice with a CD4(+) T cell-depleting Ab reduced the plasma cell, germinal center B cell, and IgG responses to ZIKV without affecting the CD8(+) T cell response. CD4(+) T cells were required to protect mice from a lethal dose of ZIKV after infection intravaginally, but not intravenously. However, adoptive transfer and peptide immunization experiments showed a role for memory CD4(+) T cells in ZIKV clearance in mice challenged intravenously. These results demonstrate that CD4(+) T cells are required mainly for the generation of a ZIKV-specific humoral response but not for an efficient CD8(+) T cell response. Thus, CD4(+) T cells could be important mediators of protection against ZIKV, depending on the infection or vaccination context. Author summary Several vaccine candidates are currently under development for Zika virus (ZIKV) infection, which causes life-threatening neurologic diseases, including congenital Zika syndrome in neonates and Guillain-Barre syndrome in adults. However, the mechanisms by which the adaptive immune system contributes to protection against ZIKV have not been fully investigated. In this report, we used mouse models of systemic and genital mucosal infection with ZIKV to evaluate the role of CD4(+) T cells in regulating antiviral humoral and CD8(+) T cell responses and in controlling ZIKV infection. We first defined the antigen specificity and phenotype of the CD4(+) T cell response to ZIKV and then demonstrated that CD4(+) T cells are required for inducing humoral, but not CD8(+) T cell, responses in ZIKV-primed mice. CD4(+) T cells were also required for local control of ZIKV burden in mice infected intravaginally. Although CD4(+) T cells are not necessary for the control of primary ZIKV infection via the intravenous route, CD4(+) T cells can confer protection against lethal intravaginal ZIKV challenge. Our results support ZIKV vaccine strategies that induce a protective CD4(+) T cell response to ZIKV.