Title: Generation of T Cell Responses and Immunological Memory Following Influenza Infection and Vaccination in Early Life and Adulthood
Description: Influenza is a significant cause of morbidity and mortality worldwide. Individuals with underlying immune conditions, including the very young, are particularly vulnerable. Infection elicits lasting antibody and T cell-mediated immune responses although antibody-mediated protection is limited due to the mutagenic nature of influenza viral surface antigens. T cell responses, in contrast, target conserved viral proteins and can protect from highly disparate strains. Compared to circulating memory, non-circulating, lung tissue-resident memory T cells (TRM) generated following influenza infection mediate enhanced viral clearance and protection following challenge. Thus, vaccination strategies promoting TRM may convey enhanced protection from disease compared to those relying on circulating responses. The factors governing TRM generation, however, are unclear and whether individuals most susceptible to infection, such as the very young, generate functional TRM is not known. This body of work investigates the nature of T cell responses and TRM establishment following influenza vaccination and infection in early life and adulthood.

We have identified distinct capacities of commercially available inactivated influenza virus (IIV) and live-attenuated influenza virus (LAIV) vaccines to elicit protective responses with IIV inducing strain-specific neutralizing antibodies and LAIV generating lung-localized, virus-specific TRM capable of providing heterosubtypic protection upon viral challenge. We have further found that infants generate robust primary T cell responses following influenza infection or LAIV vaccination comparable to adults. However, mice infected or vaccinated in infancy fail to efficiently generate TRM and are less protected from subsequent infection in adulthood. We have identified enhanced expression of T-bet, known to promote effector differentiation while limiting memory T cell establishment, by primary infant effectors and further demonstrate that heterozygous infants expressing reduced T-bet generate lung TRM comparable to adults. Together, these findings have implications in influenza vaccine design, highlighting differing mechanisms of protection between IIV and LAIV, establishing TRM as a correlate of vaccine-mediated protection to influenza, as well as identifying cell-intrinsic dysregulation of a transcriptional pathway early in life necessary for effective lung TRM generation.