UNIVERSITY OF MASSACHUSETTS
"CD4 Effector Contraction in Influenza Protective immunity depends on memory CD4 T cells generated during initial encounter with pathogen. Na?ve CD4 T cells respond vigorously to influenza (Flu) virus, expanding and differentiating into a large effector population that participates in Flu clearance indirectly by driving B cell antibody production directly in the lung. Once generated, CD8 and CD4 T effector cells migrate to the lung, virus is cleared rapidly and the CD4 effector population just as quickly contracts both in the lung and elsewhere, leaving memory CD4 T cells in peripheral sites. The contraction is necessary to limit CD4 effector-mediated immunopathology in the lung, but the factors regulating contraction are as yet unknown. Flu viruses replicate in lung epithelial cells, generating billions of viruses leading to high levels of Flu antigen (Ag) presentation and the the dramatic stimulation of the innate immune cells via recogntion of viral RNA. We postulate that these innate events result in secretion of inflammatory cytokines, including TNF and IL-6, and that these factors act on the small initial population of CD4 T cells specific for Flu, to drive a complex commitment to die when they re-encounter Ag in the lung and periphery. We have developed a model in which we study CD4 contraction, by transferring an easily identified ""indicator"" population of Flu-specific naive CD4 T cells from T cell receptor transgenic mice into a host mouse that we infect with Flu. This allows us to visualize the contraction phase by enumerating effectors in the lung at the peak of their response and just after contraction a few days later. First we will ask if Flu Ag, expressed at the initiation of contraction, is necessary to induce the process of deletion of CD4 effectors via Ag-induced cell death. Second, we will ask if inflammatory cytokines, TNF and IL-6, elaborated as a result of infection, are acting to program both the effective T cell response and the contraction phase. Third, we will ask if they accomplish this programming by increasing responding CD4 T cell production of IL-2 and IL-21."