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 ?? T cells in providing protection in the very young. These cells possess features of both the innate and adaptive arms of immunity. ?? 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 ?? 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 ?? 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 ?? 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) ?? 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 ?? 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 ?? T cells and IL-17 production upstream of a Type II immune profile that provides protection from influenza- associated disease.
These studies are based on the novel hypothesis that ?? T cells in neonates coordinate a protective immune response to influenza infection by secreting IL-17 to induce IL-33, which recruits and activates ILC2s, that in turn promote the accumulation of eosinophils, which foster clinical recovery. The elements of this hypothesis will be mechanistically tested in genetic and cell transfer-based mouse models. In aim 3, the key correlates of the findings from the animal work will be explored using a unique cohort of human samples, including valuable samples from the airways of infected infants and adults. Taken together, these studies will provide new insights into: how protective responses to influenza infection are coordinated in neonates; the function of ?? T cells in the lung and airways; comparative biology of ?? T cells between mice and humans; and, potential correlates of susceptibility in infant humans.
| Schattgen, Stefan A; Thomas, Paul G (2018) Bohemian T cell receptors: sketching the repertoires of unconventional lymphocytes. Immunol Rev 284:79-90 |
| Yang, Kai; Blanco, Daniel Bastardo; Chen, Xiang et al. (2018) Metabolic signaling directs the reciprocal lineage decisions of ?? and ?? T cells. Sci Immunol 3: |
| Guo, Xi-Zhi J; Thomas, Paul G (2017) New fronts emerge in the influenza cytokine storm. Semin Immunopathol 39:541-550 |
| Boyd, David F; Thomas, Paul G (2017) Towards integrating extracellular matrix and immunological pathways. Cytokine 98:79-86 |
