Interleukin-6 Is Crucial for Recall of Influenza-Specific Memory CD4+ T Cells

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Abstract
Currently, our understanding of mechanisms underlying cell-mediated immunity and particularly of mechanisms that promote robust T cell memory to respiratory viruses is incomplete. Interleukin (IL)-6 has recently re-emerged as an important regulator of T cell proliferation and survival. Since IL-6 is abundant following infection with influenza virus, we analyzed virus-specific T cell activity in both wild type and IL-6 deficient mice. Studies outlined herein highlight a novel role for IL-6 in the development of T cell memory to influenza virus. Specifically, we find that CD4+ but not CD8+ T cell memory is critically dependent upon IL-6. This effect of IL-6 includes its ability to suppress CD4+CD25+ regulatory T cells (Treg). We demonstrate that influenza-induced IL-6 limits the activity of virus-specific Tregs, thereby facilitating the activity of virus-specific memory CD4+ T cells. These experiments reveal a critical role for IL-6 in ensuring, within the timeframe of an acute infection with a cytopathic virus, that antigen-specific Tregs have no opportunity to down-modulate the immune response, thereby favoring pathogen clearance and survival of the host. Influenza virus poses a serious global health threat, particularly in light of newly emerging strains such as the avian virus H5N1. The generation of cell-mediated vaccines against influenza virus requires an understanding of mechanisms underlying effective virus-specific T cell memory. This study explored the impact of a cytokine, interleukin-6 (IL-6), on generation of effective influenza-specific T cell memory. This cytokine was considered important based on previous studies revealing its role in promoting survival and activity of conventional T cells whilst inhibiting the activity of T cells involved in dampening down immunity (regulatory T cells). We found that the activity of a subset of influenza-specific memory T cells (CD4+ T cells) was diminished in the absence of IL-6 due to the inhibitory effects of regulatory T cells—an effect that compromised protective anti-viral immunity. Since a robust CD4+ T cell response is likely to be central to the success of a vaccine against influenza virus, these findings highlight the importance of IL-6 in promoting effective cell-mediated immune responses, thereby facilitating successful virus clearance.