Infection order outweighs the role of CD4 + T cells in tertiary flavivirus exposure.

The link between CD4 T and B cells during immune responses to DENV and ZIKV and their roles in cross-protection during heterologous infection is an active area of research. Here we used CD4 lymphocyte depletions to dissect the impact of cellular immunity on humoral responses during a tertiary flavivirus infection in macaques. We show that CD4 depletion in DENV/ZIKV-primed animals followed by DENV resulted in dysregulated adaptive immune responses. We show a delay in DENV-specific IgM/IgG antibody titers and binding and neutralization in the DENV/ZIKV-primed CD4-depleted animals but not in ZIKV/DENV-primed CD4-depleted animals. This study confirms the critical role of CD4 cells in priming an early effective humoral response during sequential flavivirus infections. Our work here suggests that the order of flavivirus exposure affects the outcome of a tertiary infection. Our findings have implications for understanding the complex flavivirus immune responses and for the development of effective flavivirus vaccines.