Mechanisms of dysregulated immunity with aging

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DESCRIPTION (provided by applicant): Viral infections induce higher morbidity and mortality in older people than in younger individuals. Based on both experimental and clinical studies, this disease burden is thought to be due to declining immune responses. However, our published work supported by the last cycle of the award challenges this paradigm as we found that older mice exhibit dysregulated immune responses during viral infection that induce immune pathology. This dysregulation consists of exaggerated IL-17 responses produced by natural killer T (NKT) cells, innate immune lymphocytes that respond rapidly to pathogens, coupled to defective type I interferon (IFN) responses by plasmacytoid dentritic cells (pDCs), sentinel immune cells that aid viral clearance. This defective viral clearance synergizes with the age-elevated IL-17 responses leading to severe liver inflammation and death. During non-lethal systemic viral infections, exaggerated inflammatory responses (i.e., IL-6 production) by NKT-cells coupled with defective type I IFN responses by pDCs induce an inflammatory environment that skews adaptive immune CD4+ T cells to an IL-17 producing phenotype. We have also observed the age-elevated IL-17 response coupled to defective type I IFNs in other viral infections such as in localized influenza lung infections. Here, we propose to study the underlying cellular and molecular mechanisms for dysregulation of immune responses with aging by using murine models to determine 1) if exaggerated inflammatory responses by NKT cells coupled to defective pDC responses are critical for the generation of IL-17 anti-viral CD4+ T cells during systemic herpes viral infections with aging; and 2) whether exaggerated IL-17 responses by aged NKT cells coupled with impaired type I IFN responses by pDCs also induce immune pathology during influenza viral lung infection. Our work will greatly differ from mainstream research in the field and may lead to novel anti-inflammatory therapies to improve immunity to viral infections with aging.