Heterogeneity among viral antigen-specific CD4⁺ T cells and their de novo recruitment during persistent polyomavirus infection

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.