Heterogeneity among Viral Antigen-Specific CD4+ T Cells and Their De Novo Recruitment during Persistent Polyomavirus Infection

Abstract

Virus-specific CD4+ T cells optimize antiviral responses by providing help for antiviral humoral responses and CD8+ T cell differentiation. Although CD4+ T cell responses to viral infections that undergo complete clearance have been studied extensively, less is known about virus-specific CD4+ T cell responses to viruses that persistently infect their hosts. Using a mouse polyomavirus (MPyV) infection model, we previously demonstrated that CD4+ T cells are essential for recruiting naive MPyV-specific CD8+ T cells in persistently infected mice. In this study, we defined two dominant MPyV-specific CD4+ T cell populations, one directed toward an epitope derived from the nonstructural large T Ag and the other from the major viral capsid protein of MPyV. These MPyV-specific CD4+ T cells vary in terms of their magnitude, functional profile, and phenotype during acute and persistent phases of infection. Using a minimally myeloablative-mixed bone marrow chimerism approach, we further show that naive virus-specific CD4+ T cells, like anti-MPyV CD8+ T cells, are primed de novo during persistent virus infection. In summary, these findings reveal quantitative and qualitative differences in the CD4+ T cell response to a persistent virus infection and demonstrate that naive antiviral CD4+ T cells are recruited during chronic polyomavirus infection.