Abstract
Influenza A virus (IAV) is a leading cause of respiratory infections, with increased risk of severe illness and death in the very young, aged, and immunocompromised individuals. In both mice and humans, IAV-specific T cell responses are protective during primary as well as homologous and heterologous challenge infections. Many mouse studies have focused on CD4 T cells specific for a single, known model or IAV antigen. However, studies have demonstrated that the IAV-specific CD4 T cell response comprises many epitopes spread across multiple viral proteins. Therefore, herein we track the antigen-experienced CD4 T cell response using the surrogate markers CD49d and CD11a. This novel surrogate marker method allows us to characterize the full IAV-specific CD4 T cell response without the potential bias that could occur when examining an individual Ag-specificity. Our findings demonstrate that the immunodominant I-Ab-binding NP311−325 epitope often used in studies of IAV-specific CD4 T cells represents only about 5% of the total IAV-specific CD4 T cell response. Further, we find that the kinetics of the full pulmonary CD4 T cell response is similar to that of NP311-specific T cells and that the full CD4 T cell response in the lungs is predominantly composed of cells expressing the Th1 transcription factor T-bet, with smaller but significant portions of the response expressing the Treg and Tfh associated transcription factors Foxp3 and Bcl-6, respectively. Interestingly, although Th1 cells are the most abundant Th subset in the lungs of both BALB/c and C57Bl/6 mice following IAV, the relative abundance of Treg and Tfh is reversed in the different mouse strains. In BALB/c mice, Foxp3+ cells are more abundant than Bcl6+ cells, whereas in C57Bl/6 mice, there are more Bcl6+ cells. As a whole, these data highlight the diversity of the endogenous CD4 T cell response to a primary IAV infection, providing an important context for past and future studies of the IAV-specific CD4 T cell response.
Highlights
Influenza A virus (IAV) is a major cause of respiratory infection, leading to ∼200,000 hospitalizations and 36,000 deaths in the United States each year [1]
In order to begin to clarify the kinetics of the endogenous CD4 T cell response to IAV, we quantified NP311-specific CD4 T cells [tetramer+ (Figure 1A) and IFNγ+ (Figure 1B)] during a primary IAV infection
We demonstrate that while the endogenous NP311-specific CD4 T cell response is largely IFNγfocused, with cells presumably belonging to the Th1 subset, NP311-specific CD4 T cells represent only a small fraction of the total antigen-experienced CD4 T cells in the lungs following infection
Summary
Influenza A virus (IAV) is a major cause of respiratory infection, leading to ∼200,000 hospitalizations and 36,000 deaths in the United States each year [1]. Annual vaccination effectively induces antibody responses that can protect the host against infection with homologous viruses; more recent findings have indicated that IAV-specific T cells generated following vaccination. Much of our understanding of the role of individual IAV-specific CD4 T helper subsets in the immune response to influenza virus comes from studies using adoptive transfer of TCR transgenic IAV-specific CD4 T cells or after in vitro activation and differentiation of IAV-specific T cells using a single or limited number of known IAV epitopes [8, 10, 14, 16,17,18]. It currently remains unclear how representative the findings from studies utilizing T cells specific for a single or limited number of epitopes are of the full diverse endogenous CD4 T cell response to influenza virus
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