CD8 ⁺ T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection

Abstract

Zika virus (ZIKV) infection causees neurologic complications, includingGuillain-Barré syndrome in adults and central nervous system (CNS) abnormalities in fetuses. We investigated the immune response, especially the CD8 ϩ T cell response in C57BL/6 (B6) wild-type (WT) mice, during ZIKV infection. We found that a robust CD8 ϩ T cell response was elicited, major histocompatibility complex class I-restricted CD8 ϩ T cell epitopes were identified, a tetramer that recognizes ZIKV-specific CD8 ϩ T cells was developed, and virus-specific memory CD8 ϩ T cells were generated in these mice. The CD8 ϩ T cells from these infected mice were functional, as evidenced by the fact that the adoptive transfer of ZIKV-specific CD8 ϩ T cells could prevent ZIKV infection in the CNS and was cross protective against dengue virus infection. Our findings provide comprehensive insight into immune responses against ZIKV and further demonstrate that WT mice could be a natural and easy-access model for evaluating immune responses to ZIKV infection.IMPORTANCE ZIKV infection has severe clinical consequences, including GuillainBarré syndrome in adults, microcephaly, and congenital malformations in fetuses and newborn infants. Therefore, study of the immune response, especially the adaptive immune response to ZIKV infection, is important for understanding diseases caused by ZIKV infection. Here, we characterized the CD8 ϩ T cell immune response to ZIKV in a comprehensive manner and identified ZIKV epitopes. Using the identified immunodominant epitopes, we developed a tetramer that recognizes ZIKVspecific CD8 ϩ T cells in vivo, which simplified the detection and evaluation of ZIKVspecific immune responses. In addition, the finding that tetramer-positive memory CD8 ϩ T cell responses were generated and that CD8 ϩ T cells can traffic to a ZIKVinfected brain greatly enhances our understanding of ZIKV infection and provides important insights for ZIKV vaccine design.KEYWORDS CD8 ϩ T cell, ZIKV, central nervous system, cross protection, immunocompetent mouse model Z ika virus (ZIKV) is a mosquito-transmitted flavivirus and a member of the Flaviviridae family of positive-stranded RNA enveloped viruses; the virus has also been found to be sexually and vertically transmitted (1). It was identified in 1947 in sentinel monkeys in Uganda (2). After its introduction into Brazil in 2015, ZIKV spread rapidly, both (i) causing a mild syndrome characterized by self-limiting fever, headache, myalgia, rash, and conjunctivitis and (ii) resulting in severe clinical consequences, including Guillain-

The continued threat of emerging flaviviruses

“…Heterologous, memory T-cell responses also can have protective functions, as cross-reactive DENV-immune CD8 + T cells restrict ZIKV infection and disease, including in pregnancy 126,127 . Reciprocally, ZIKV-immune CD8 + T cells can protect against DENV infection in mice 128 .…”

Mathematical modeling of within‐host Zika virus dynamics

“…T‐cell responses have also been shown to be capable of providing protection against ZIKV infection. In immunocompetent mice infected with ZIKV, a T cell response is seen by 7 days postinfection, with antigen‐specific IFNγ‐producing CD8 T cells generated . These CD8 T cells, on transfer to IFNα receptor knockout mice, protect from weight loss and reduce ZIKV burden after infection.…”

Recombinant Chimpanzee Adenovirus Vaccine AdC7-M/E Protects against Zika Virus Infection and Testis Damage

“…4D and E) were detected in the AdC7-M/E group, demonstrating an immunodominant role of ZIKV E protein. To further evaluate the cellular immunogenicity of the AdC7-M/E vaccine, tetramers consisting of two peptides derived from the ZIKV M (residues 251 to 259; M 251-259 ) and E (residues 294 to 302; E 294 -302 ) proteins were prepared as described previously (53) and used to detect and quantify antigen-specific CD8 ϩ T cells. A high proportion (1.88% Ϯ 0.36%) of M 251-259 tetramer-positive ( Fig.…”