A promising new vaccine strategy is to optimize antigen presentation and elicit desired T cell responses by targeting immunogens to specific dendritic cell (DC) subsets. Such vaccinations are especially promising for respiratory infections such as influenza virus, since resident DCs in nasal and lung tissue are crucial for initiation of beneficial immune responses after infection or vaccination. The success of this strategy requires understanding how the development and functional responses of specific DC subsets present in nasal tissue and lung are regulated. Specific transcription factors expressed in DC progenitors govern the development of each DC subset during homeostasis, but how these transcription factors regulate de novo DC development and mature DC function during viral infection is not known. Our objective here is to determine how the transcription factor interferon regulatory factor 4 (IRF4) regulates de novo development and functional responses of lung DC subsets during influenza virus infection. To further elucidate the role of IRF4, we have developed CD11c-cre-Irf4fl mice in which 0, 1 or 2 copies of a conditional Irf4fl allele are deleted specificlly in CD11c+ pre-cDCs and mature DCs. Our preliminary studies with this novel model suggest that IRF4 is required for the development of a lung resident CD11b+ DC subset. Upon influenza virus infection, the absence of this lung DC subset leads to an altered cytokine profile of lung DCs, reduced numbers of IFN?-producing influenza- specific CD8+ T cells and increased severity of infection. Based on these data, we propose the central hypothesis that quantitative differences in IRF4 regulate de novo differentiation of lung CD11b+ DCs and shape functional responses of mature lung DCs during influenza virus infection of mice. To test this hypothesis and define the mechanisms regulating DC development and function, we will use our new murine model to dissect the effects of pre-cDC- and DC-restricted IRF4 deficiency and haploinsufficiency on DC-mediated responses in vivo. The successful completion of this project is likely to provide new information that will support the development of DC subset-targeting strategies for human pulmonary vaccination against pandemic influenza viruses and other respiratory pathogens.

R01HL119501

2014-09-01

2019-07-31