Lung γδ T Cells Mediate Protective Responses during Neonatal Influenza Infection that Are Associated with Type 2 Immunity

Compared to adults, infants suffer higher rates of hospitalization, severe clinical complications, and mortality due to influenza infection. We found that gamma delta T cells protected neonatal mice against mortality during influenza infection. gamma delta T cell deficiency did not alter viral clearance or interferon-gamma production. Instead, neonatal influenza infection induced the accumulation of interleukin-17A (IL-17A)-producing gamma delta T cells, which was associated with IL-33 production by lung epithelial cells. Neonates lacking IL-17A-expressing gamma delta T cells or Il33 had higher mortality upon influenza infection. gamma delta T cells and IL-33 promoted lung infiltration of group 2 innate lymphoid cells and regulatory T cells, resulting in increased amphiregulin secretion and tissue repair. In influenza-infected children, IL-17A, IL-33, and amphiregulin expression were correlated, and increased IL-17A levels in nasal aspirates were associated with better clinical outcomes. Our results indicate that gamma delta T cells are required in influenza-infected neonates to initiate protective immunity and mediate lung homeostasis.