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

• Published in: PLoS pathogens 2019-01, Vol.15 (1), p.e1007474-e1007474
• Main Authors: Elong Ngono, Annie, Young, Matthew P, Bunz, Maximilian, Xu, Zhigang, Hattakam, Sararat, Vizcarra, Edward, Regla-Nava, Jose Angel, Tang, William W, Yamabhai, Montarop, Wen, Jinsheng, Shresta, Sujan
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animal models; Animals; Antibodies; Antibodies, Viral - blood; Antibody response; Biology; Biology and Life Sciences; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cytotoxicity; Dengue fever; Epidemics; Epitopes; Epitopes, T-Lymphocyte - immunology; Guillain-Barre syndrome; Humoral immunity; Immune response (humoral); Immunity; Immunity, Humoral - immunology; Immunization; Immunoglobulin G; Immunological memory; Immunology; Infections; Inflammation; Interferon; Intravenous administration; Investigations; Lethal dose; Lymphocytes; Lymphocytes B; Lymphocytes T; Medicine and Health Sciences; Memory cells; Mice; Mice, Inbred C57BL; Peptides; Phenotypes; Proteins; Research and Analysis Methods; Supervision; Vaccination; Vaccines; Vector-borne diseases; Viral Vaccines - immunology; Virus Diseases - metabolism; Viruses; West Nile virus; Zika virus; Zika Virus - immunology; Zika Virus Infection - immunology; Zika Virus Infection - virology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007474

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+Ifnar1fl/fl (myeloid type I IFN receptor-deficient) C57BL/6 mouse models, we identified six I-Ab-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.