Reduced lung-resident T cell memory in infants following influenza infection

Abstract

Abstract Influenza is a major cause of morbidity and mortality in infants, who suffer more severe disease and are more susceptible to reinfection. In adults, influenza generates robust lung tissue-resident T cell memory (TRM) populations which are protective upon subsequent infection. Using a mouse model, we investigated whether infants also establish lung TRM after influenza infection. We found that infants and adults mount similar primary lung T cell responses to influenza. However, following recovery, infected infants generated fewer lung TRM than did animals infected as adults. Mice infected as infants also suffered greater weight loss and increased lung viral titers upon reinfection as adults in a TRM-dependent manner. Reciprocal transfer of infant or adult antigen-specific CD4 T cells to adult or infant hosts revealed that while both infant and adult cells expand in the primary response, only adult cells are efficiently maintained as TRM after resolution of infection suggesting a cell-intrinsic cause for reduced TRM in infants. RNAseq analysis of infant and adult primary effectors revealed increased T-bet and strongly decreased levels of Eomes and the survival factor Bcl-2 in infant T cells while analysis of protected lung memory from animals infected as infants or adults demonstrated lower levels of TRM-associated retention markers and decreased levels of the survival factors Bcl-2 and Bcl-xL. Further pathway analysis implicated reduced IL-7 and IL-15 signaling in infant T cells suggesting a mechanism for their reduced TRM with important implications in vaccine design and therapies for influenza in this population.