CD8+ T cells are crucial for humoral immunity establishment by SA14‐14‐2 live attenuated Japanese encephalitis vaccine in mice

• Published in: European journal of immunology Vol. 51; no. 2; pp. 368 - 379
• Main Authors: Kalia, Anurag, Agrawal, Mona, Gupta, Nimesh
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.02.2021
• Subjects: Animal models; Animals; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antibody response; Antigens, Viral - immunology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Correlates‐of‐protection; Encephalitis; Encephalitis Virus, Japanese - immunology; Encephalitis, Japanese - immunology; Flavivirus vaccine; Helper cells; Humoral immunity; Immunity, Humoral - immunology; Japanese encephalitis; Japanese Encephalitis Vaccines - immunology; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Neutralizing antibody; Tfh cells; Vaccination - methods; Vaccines; Vaccines, Attenuated - immunology; Correlates-of-protection; Flavivirus vaccine; Tfh cells; Neutralizing antibody; Japanese encephalitis
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.202048745

The live attenuated SA14‐14‐2 Japanese encephalitis (JE) vaccine is a historical vaccine that protects against JE. Despite its extensive use, the mechanism of protective immunity conferred by the SA14‐14‐2 vaccine is not well established. Here, we used mouse models to understand the mechanism of the development of humoral immunity against the vaccine. The vaccine induces robust GC responses within a week postimmunization. In lethal virus challenge, we show that CD4+ T cells alone, but not CD8+ T cells, are sufficient to confer vaccine‐mediated protection. However, the CD4‐mediated protection was potentiated in the presence of vaccine‐primed CD8+ T cells. Employing CD8‐deficient mice, we show that both the protective traits of CD4+ T cells and the quality of antibody response to the vaccine are impaired in absence of CD8+ T cells. We further demonstrate that the poor protective immune response induced by the vaccine in absence of CD8+ T cells is mainly due to the impaired differentiation and function of follicular Th cells, leading to suboptimal GC reaction. Our study highlights an unprecedented role of CD8+ T cells in the establishment of humoral responses to the vaccine. By elucidating underlying cellular determinants of vaccine‐induced protective immunity, our work has implications for rational design of vaccines against JE virus and related flaviviruses. SA14‐14‐2 JE vaccine induced protective humoral immunity is largely dependent on CD4+ T cells and is augmented by CD8+ T cells. Vaccine‐primed CD8+ T cells are not protective but influence GC‐Tfh differentiation and the productive GC response. We implicate follicular CD8+ T cells in shaping the GC response to the vaccine.