A protective role for gamma delta T cells in respiratory infection

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 DESCRIPTION (provided by applicant): Children under 2 are a high risk group for severe morbidity and mortality after respiratory infections, including influenza. In addition to lacking years of immunological experience and memory responses, neonatal and infant immune systems have other qualitative and quantitative distinctions from adults. In this proposal, we will examine a special role for γδ T cells in providing protection in the very young. These cells possess features of both the innate and adaptive arms of immunity. γδ T cells have not been extensively studied during influenza infection, and the mechanisms by which these cells protect the respiratory mucosa are not known. Published reports suggest a relatively limited role in promoting inflammation; however, these studies were done in adult animals. Our preliminary data indicate that γδ T cells play a necessary role in the survival of neonates after influenza infection, perhaps due to the immaturity of other immune effectors. This protection depends on γδ T cell-induced IL-33 production. IL-33 regulates ILC2 activity and eosinophil recruitment, bot of which play roles in restoring epithelial integrity. The central hypothesis of this proposal is tat γδ T cells initiate an immune cascade that promotes survival in neonatal influenza infection via the recruitment and activation of ILC2s and eosinophils. Our three aims test the specific hypotheses that 1) γδ T cell promote survival after influenza infection in neonatal mice by secreting IL-17, which leads to the induction of IL-33 from lung epithelial cells, 2) that IL-33 downstream of γδ T cell activation leads to ILC2 activation and eosinophil accumulation, which are necessary for recovery of lung function in neonates, and 3) that a similar regulatory network is operating in humans, which we will test using a valuable repository of clinical human isolates. These experiments will define a distinct protective mechanism operating in the very young, establishing a role for γδ T cells and IL-17 production upstream of a Type II immune profile that provides protection from influenza- associated disease.