Abstract
The adaptive T cell response to influenza B virus is understudied, relative to influenza A virus, for which there has been considerable attention and progress for many decades. Here, we have developed and utilized the C57BL/6 mouse model of intranasal infection with influenza B (B/Brisbane/60/2008) virus and, using an iterative peptide discovery strategy, have identified a series of robustly elicited individual CD4 T cell peptide specificities. The CD4 T cell repertoire encompassed at least eleven major epitopes distributed across hemagglutinin, nucleoprotein, neuraminidase, and non-structural protein 1 and are readily detected in the draining lymph node, spleen, and lung. Within the lung, the CD4 T cells are localized to both lung vasculature and tissue but are highly enriched in the lung tissue after infection. When studied by flow cytometry and MHC class II: peptide tetramers, CD4 T cells express prototypical markers of tissue residency including CD69, CD103, and high surface levels of CD11a. Collectively, our studies will enable more sophisticated analyses of influenza B virus infection, where the fate and function of the influenza B-specific CD4 T cells elicited by infection and vaccination can be studied as well as the impact of anti-viral reagents and candidate vaccines on the abundance, functionality, and localization of the elicited CD4 T cells.
Highlights
We examined influenza A/California/04/2009 (IAV), an H1N1 virus that emerged in humans in 2009 influenza A/California/04/2009 (IAV), an H1N1 virus that emerged in humans in 2009 parallel, which we have previous studied in mouse models of infection [61,62]
These strains of recent human isolates of influenza virus have not been modified by adaptat strains of recent human isolates of influenza virus have not been modified by adaptation in mice, unlike other commonly used IAV viruses such as the H1N1 A/Puerto Rico/8 in mice, unlike other commonly used IAV viruses such as the H1N1 A/Puerto Rico/8/34 (PR8) or A/HKx31 (X31) H3N2 viruses
After establishing experimental conditions to infect the B6 mice, we evaluated the kinetics of recruitment of CD4 T cells so that we could assess elicitation of CD4 T cells at the peak of the response, and we found that day 10–11 post infection was the optimal point to sample tissues for the isolation of CD4 T cells
Summary
Animal models of influenza infection and vaccination are tremendously valuable for exploring issues related to influenza virus biology, transmission, immunity to infection, and to the development of protective vaccines. These models have been used to characterize the kinetics of infection and viral clearance, elicitation of innate and adaptive responses, testing of antiviral compounds, and for preclinical studies of vaccine candidates. Animal models permit invasive sampling of tissues, such as lung and lymph nodes, in order to analyze events such as the germinal center response and tissue-resident immunity. Giving the Genes a Shuffle: Using Natural Variation to Understand Host Genetic Contributions to Viral
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