Antibody-independent antiviral function of memory CD4(+) T cells in vivo requires regulatory signals from CD8(+) effector T cells

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 clearan ce, are poorly understood. Here we show that control of a Sendai virus infe ction by primed CD4(+) T cells is mediated through the production of IFN-ga mma 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 recr uitment of memory CD4(+) T cells to the lungs. Passive transfer of a CD8(+) T cell supernatant into CD8(+) T cell-depleted, hemagglutinin-neuraminidas e (HN)(421-436)-immune mu MT mice substantially restored the virus-specific memory CD4(+) response and enhanced viral control in the lung. Together, t he data demonstrate for the first time that in vivo primed CD4(+) T cells h ave 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 o f 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.