Research Project
8135009
DESCRIPTION (provided by applicant): Background: CD4+ T-cells are involved in the immune response to influenza infection by not only providing help for B-cells and CD8+ T-cells, but also by exhibiting direct antiviral effector functions. These antiviral functions could have a dramatic impact on the integrity of the airway epithelium by increasing the damage caused by the responding immune response to the surrounding epithelial cells in the lungs. CD4+ T-cells can secrete interferon-? (Th1) upon viral antigen encounter but the role of Th1 or other pro- inflammatory CD4+ T-cells, such as subsets secreting interleukin-17, in mediating immunopathology during influenza infection has not been fully delineated. Influenza infection generates robust CD4+ T-cell memory, with rapid antiviral effector functions, that cross-reacts with numerous conserved internal epitopes shared between viral strains. A comparative study of the key CD4+ T-cell subsets and their mechanisms that promote tissue damage and/or protection from virus during a primary versus secondary response is therefore warranted. Methods: C57BL/6NCr will be infected with influenza A/PR8/34 (PR8) and rested for six weeks post-infection to generate CD4+ T-cell memory for adoptive transfer. C57BL/6NCr mice with either no previous memory (primary infection) or having PR8 specific lung and spleen adoptively transferred CD4+ T-cell memory will be infected with the heterosubtypic strain of influenza A/HK-x31 (X31). Specific Aims: We will investigate the role and mechanisms involved in the promotion of pulmonary inflammation by memory CD4 T-cells during secondary responses to influenza using the murine model. Therefore, we have generated two specific aims: Aim I: Determine how memory CD4 T-cells interact with lung epithelium during influenza challenge to promote immunopathology and Aim II: Determine the pro-inflammatory role of memory CD4 T-cell subtypes and protective responses in lungs during a secondary response to influenza infection. Summary: This study will explore an immunopathologic and/or protective role for CD4+ T-cells during influenza infection and define the mechanisms involved that could enhance lung epithelial damage. This study could have a profound effect on vaccination or therapeutic strategies that enhance protection but limit immunopathologic responses.
