The antiviral CD8⁺ T cell response is differentially dependent on CD4⁺ T cell help over the course of persistent infection

Although many studies have investigated the requirement for CD4⁺ T cell help for CD8⁺ T cell responses to acute viral infections that are fully resolved, less is known about the role of CD4⁺ T cells in maintaining ongoing CD8⁺ T cell responses to persistently infecting viruses. Using mouse polyoma virus (PyV), we asked whether CD4⁺ T cell help is required to maintain antiviral CD8⁺ T cell and humoral responses during acute and persistent phases of infection. Though fully intact during acute infection, the PyV-specific CD8⁺ T cell response declined numerically during persistent infection in MHC class II-deficient mice, leaving a small antiviral CD8⁺ T cell population that was maintained long term. These unhelped PyV-specific CD8⁺ T cells were functionally unimpaired; they retained the potential for robust expansion and cytokine production in response to Ag rechallenge. In addition, although a strong antiviral IgG response was initially elicited by MHC class II-deficient mice, these Ab titers fell, and long-lived PyV-specific Ab-secreting cells were not detected in the bone marrow. Finally, using a minimally myeloablative mixed bone marrow chimerism approach, we demonstrate that recruitment and/or maintenance of new virus-specific CD8⁺ T cells during persistent infection is impaired in the absence of MHC class II-restricted T cells. In summary, these studies show that CD4⁺ T cells differentially affect CD8⁺ T cell responses over the course of a persistent virus infection.