Immunosuppressive factors in the neonatal immune response to influenza virus

Influenza virus causes more infant deaths than any other vaccine preventable disease. The neonatal immune system has been described as naive and immature resulting in suboptimal antigen presentation. Neonatal T cells have an intrinsic T helper 2 (Th2) bias, however Th2 responses are not protective against influenza virus. Instead a T helper 1 (Th1) response is required for influenza viral clearance in adults. We propose that neonates are more susceptible to influenza virus due to inadequate T cell polarization driven by immature dendritic cell (DC) co-stimulation. In adult mice, DCs prime CD8 T cells for rapid influenza viral clearance. Neonatal CD8 T cells recognize different epitopes of influenza virus than adult CD8 T cells. Neonatal mice have lower proportions of DCs than adults and significantly less type I interferon alpha, a cytokine necessary for priming an anti-viral immune responses. Influenza viral clearance was enhanced in the neonatal lung when primed with mature adult bone marrow derived DCs. These data suggest that immature DCs in neonatal mice contribute to delayed influenza viral clearance and skewed CD8 T cell specificity.;Dendritic cells must activate and be activated by CD4 T helper cells prior to priming antigen specific CD8 T cell responses against influenza virus. Neonatal CD4 T cells transferred into adult T cell receptor deficient mice were less activated and did not expand to adult CD4 T cell numbers in the lung digest. Neonatal mice had similar proportions of T helper 17 cells (Th17) but more T regulatory cells (Tregs) in the lung digest than adult mice. Neutralization of interleukin 17a (IL-17a), a Th17 cytokine, decreased the number of neutrophils in the airways, but had no effect on influenza viral burden. Neonatal mice lacking Tregs had significantly more antigen specific CD8 T cells, more Th1 and Th17 cells. However, neonatal mice lacking Tregs also had a higher viral burden and significantly increased proportions of CD4 T helper cells expressing interleukin 13, a Th2 cytokine. These data suggests that Tregs alter DC priming of antigen specific CD8 T cells but are important for restraining Th2 responses in neonatal mice enabling influenza viral clearance.;KEYWORDS: Neonates, Influenza virus, T cells, Lung, and Transforming growth factor beta.;Multimedia Elements Used: Tag Image File Format (.TIF).