This proposal is based on our recent studies that IRF4 plays an essential role in sustaining cytotoxic T lymphocyte (CTL) expansion and effector differentiation during influenza infection. In this application, we will further investigate the celular mechanisms by which IRF4 controls the quantity and quality of CTL responses during influenza infection. In addition, we hypothesize that the defective IRF4 expression in infant T cells constitutes a major barrier for the efficient development of both cellular and humoral immunity in infants following immunization. We believe that the manipulation of IRF4 expression and function may serve as a potential strategy to boost both humoral and cellular immunity in infants.
Two specific aims are proposed:
Aim1 : To elucidate the mechanisms through which IRF4 modulates the quantity and quality of anti-viral CTL responses.
Aim2 : To determine the role of impaired IRF4 expression in T cells in infant immunity. Relevance statement Influenza virus is a tremendous source of morbidity and mortality for the human population, especially in infants. CD8 cytotoxic T lymphocytes (CTLs) play an important role in the control of influenza virus infections and the generation of a cross-reactive CTL-based vaccine remains a viable vaccine option for the prevention/amelioration of future pandemics. However, current understanding the molecular mechanisms regulating the efficient development of CD8 T cell-mediated immunity to influenza infection is still largely elusive. The successful completion of thi application thus will significant advance our understanding on the induction of effective CTL responses during primary influenza infection. Furthermore, the knowledge generated from these studies will improve our understanding of the molecular mechanisms underlying the defects in both cellular and humoral immunity in infants. In addition, we expect that this application will establish principles that could be utilized in the future to improve the efficacy of influenza and other pathogen vaccines in infants.
Influenza virus is the leading cause of upper and lower respiratory infection, and constitutes an ongoing threat to global health. The goals of this application are to dissect the cellular and molecular mechanisms by which effective antiviral T cell immunity is induced during influenza infection, and to use immunological and pharmacological tools to simultaneously boost both cellular and humoral immunity to increase vaccine efficacy in infants.
