Antibody-Independent Antiviral Function of Memory CD4+ T Cells In Vivo Requires Regulatory Signals from CD8+ Effector T Cells

Abstract

Previous studies have shown that vaccine-primed CD4+ T cells can mediate accelerated clearance of respiratory virus infection. However, the relative contributions of Ab and CD8+ T cells, and the mechanism of viral clearance, are poorly understood. Here we show that control of a Sendai virus infection by primed CD4+ T cells is mediated through the production of IFN-γ and does not depend on Ab. This effect is critically dependent on CD8+ cells for the expansion of CD4+ T cells in the lymph nodes and the recruitment of memory CD4+ T cells to the lungs. Passive transfer of a CD8+ T cell supernatant into CD8+ T cell-depleted, hemagglutinin-neuraminidase (HN)421–436-immune μMT mice substantially restored the virus-specific memory CD4+ response and enhanced viral control in the lung. Together, the data demonstrate for the first time that in vivo primed CD4+ T cells have the capacity to control a respiratory virus infection in the lung by an Ab-independent mechanism, provided that CD8+ T cell “help” in the form of soluble factor(s) is available during the virus infection. These studies highlight the importance of synergistic interactions between CD4+ and CD8+ T cell subsets in the generation of optimal antiviral immunity.