Differential T Cell Responses to Residual Viral Antigen Prolong CD4+ T Cell Contraction following the Resolution of Infection

Abstract

The contraction phase of the T cell response is a poorly understood period after the resolution of infection when virus-specific effector cells decline in number and memory cells emerge with increased frequencies. CD8+ T cells plummet in number and quickly reach stable levels of memory following acute lymphocytic choriomeningitis virus infection in mice. In contrast, virus-specific CD4+ T cells gradually decrease in number and reach homeostatic levels only after many weeks. In this study, we provide evidence that MHCII-restricted viral Ag persists during the contraction phase following this prototypical acute virus infection. We evaluated whether the residual Ag affected the cell division and number of virus-specific naive and memory CD4+ T cells and CD8+ T cells. We found that naive CD4+ T cells underwent cell division and accumulated in response to residual viral Ag for >2 mo after the eradication of infectious virus. Surprisingly, memory CD4+ T cells did not undergo cell division in response to the lingering Ag, despite their heightened capacity to recognize Ag and make cytokine. In contrast to CD4+ T cells, CD8+ T cells did not undergo cell division in response to the residual Ag. Thus, CD8+ T cells ceased division within days after the infection was resolved, indicating that CD8+ T cell responses are tightly linked to endogenous processing of de novo synthesized virus protein. Our data suggest that residual viral Ag delays the contraction of CD4+ T cell responses by recruiting new populations of CD4+ T cells.