Abstract
Zika virus (ZIKV), a flavivirus with homology to dengue virus (DENV), is spreading to areas of DENV hyper-endemicity. Heterologous T cell immunity, whereby virus-specific memory T cells are activated by variant peptides derived from a different virus, can lead to enhanced viral clearance or diminished protective immunity and altered immunopathology. In mice, CD8+ T cells specific for DENV provide in vivo protective efficacy against subsequent ZIKV infection. In humans, contrasting studies report complete absence or varying degrees of DENV/ZIKV T cell cross-reactivity. Moreover, the impact of cross-reactive T cell recognition on the anti-viral capacity of T cells remains unclear. Here, we show that DENV-specific memory T cells display robust cross-reactive recognition of ZIKV NS3 ex vivo and after in vitro expansion in respectively n = 7/10 and n = 9/9 dengue-immune individuals tested. In contrast, cross-reactivity toward ZIKV capsid is low or absent. Cross-reactive recognition of DENV or ZIKV NS3 peptides elicits similar production of the anti-viral effector mediators IFN-γ, TNF-α, and CD107a. We identify 9 DENV/ZIKV cross-reactive epitopes, 7 of which are CD4+ and 2 are CD8+ T cell epitopes. We also show that cross-reactive CD4+ and CD8+ T cells targeting novel NS3 epitopes display anti-viral effector potential toward ZIKV-infected cells, with CD8+ T cells mediating direct lyses of these cells. Our results demonstrate that DENV NS3-specific memory T cells display anti-viral effector capacity toward ZIKV, suggesting a potential beneficial effect in humans of pre-existing T cell immunity to DENV upon ZIKV infection.
Highlights
We first investigated the extent of cross-reactive T cell recognition of Zika virus (ZIKV) antigens by dengue-specific memory T cells and asked whether cross-reactivity could be detected in both CD4+ and CD8+ T cell compartments
Due to cell number limitations of our samples we focused our study on the structural protein capsid and the nonstructural protein NS3, which represent the main targets of the CD4+ and CD8+ (NS3) T cell response to dengue virus (DENV) [33,34,35]
Cross-reactive recognition of ZIKV capsid was detected only for the CD4+ T cell subset albeit at significantly lower levels compared to its DENV counterpart (Figure 1C)
Summary
Our results demonstrate that DENV NS3-specific memory T cells display anti-viral effector capacity toward ZIKV, suggesting a potential beneficial effect in humans of pre-existing T cell immunity to DENV upon ZIKV infection. Recent studies have shown that human DENV E protein-reactive antibodies crossreact with ZIKV but are poorly neutralizing and instead potently enhance ZIKV infection in vitro, through a mechanism termed antibody dependent enhancement [10, 11] One of these studies addresses whether cross-reactive T cells could play a similar detrimental role upon ZIKV infection, no evidence of cross-reactive CD4+ T cell recognition between DENV and ZIKV envelope and NS1 proteins is found [10]. These data support findings from the mouse studies and point toward a potential beneficial role of dengue-specific crossreactive T cells during ZIKV infection
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