Human influenza A-specific memory T cells reside within multiple tissues and elicit a tissue-specific antiviral response when presented with viral antigens

Abstract

Abstract Generation of memory T cells specific for conserved viral epitopes provides heterosubtypic protection to influenza infection. Previous mouse studies have shown that tissue-resident memory T cells (TRM) are critical for optimal protection. However, knowledge of human antiviral response is largely derived from blood. With our unique human donor tissue resource established in collaboration with LiveOnNY, we investigate the maintenance of influenza-specific T cells across diverse tissue sites and their response when presented with viral antigens. Using multimer staining and flow cytometry, we show that influenza-specific CD8 T cells are maintained in the lung tissue site of infection, as well as in blood, bone marrow, multiple lymph nodes, and small intestines. Compared to T cells recognizing persistent cytomegalovirus infection, influenza-specific T cells display higher levels of canonical residency markers—CD69 and CD103. Additionally, deep sequencing of the T cell receptor CDR3b repertoire reveals that influenza-specific T cells isolated from human tissue donors without active infection are clonally expanded and display a high degree of clonal overlap across tissue sites. When presented with viral antigens, influenza-specific T cells in all sites are polyfunctional and rapidly respond through cytokine production. Together, these studies reveal the dynamics of immune memory maintenance and antiviral response across tissues in the human body in response to influenza A virus.