The influenza virus is a common pathogen of humans with the ability to cause death in the young and immunocompromised. Even though influenza continues to be a great threat to human life, much still needs to be learned about immunity to the virus and how immunity is maintained. To date most studies examining cell responses to influenza have examined peripheral blood and have shown that humans expressing HLA-A2 have a focused T cell response with the majority of T cells using Vbeta17 and recognize residues 58-66 of the influenza protein MI. However, this response is very complex as shown by the number large number of sequences that comprise the CDR3. As a general rule immune responses become more focused and less complex upon repeated antigen exposure. Thus in the lung, at the site of influenza infection, we would expect the influenza-specific T cell repertoire to be more focused and less complex. This hypothesis will be tested in this proposal in three specific aims.
In aim 1 we will compare the influenza-specific T cell repertoire in the blood and lung of normal controls and influenza-infected individuals to examine whether the memory T cells in the lung express TCR sequences that are similar or less complex than those in the blood. In the second aim, because certain experiments cannot be performed on humans, we will develop an animal model to study the generation and maintenance of T cell repertoires upon repeated exposure to antigen. In the third aim, we will expand our studies beyond alpha/beta T cells and characterize gamma/delta T cells that reside in the lung in normal and influenza-infected individuals. Gamma/delta T cells are of interest because they are known to regulate alpha/beta T cell responses and can bridge the innate with the adaptive immune response. Little is known about the role of gamma/delta T cells in influenza immunity. These collective studies are designed to further our knowledge of human immunology, by acquiring information on influenza immunity in the lung, the tissue most affected by influenza infection.
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