Host Differences in Influenza-Specific CD4 T Cell and B Cell Responses Are Modulated by Viral Strain and Route of Immunization

Aarthi Sundararajan,Hyemee Joo,Andrea J Sant,Lifang Huan,Glendie Marcelin,Richard J Webby,Shabnam Alam,Katherine A Richards,Hongmei Yang,David J Topham,Mark Y Sangster,Steven M Varga

doi:10.1371/journal.pone.0034377

Abstract

The antibody response to influenza infection is largely dependent on CD4 T cell help for B cells. Cognate signals and secreted factors provided by CD4 T cells drive B cell activation and regulate antibody isotype switching for optimal antiviral activity. Recently, we analyzed HLA-DR1 transgenic (DR1) mice and C57BL/10 (B10) mice after infection with influenza virus A/New Caledonia/20/99 (NC) and defined epitopes recognized by virus-specific CD4 T cells. Using this information in the current study, we demonstrate that the pattern of secretion of IL-2, IFN-γ, and IL-4 by CD4 T cells activated by NC infection is largely independent of epitope specificity and the magnitude of the epitope-specific response. Interestingly, however, the characteristics of the virus-specific CD4 T cell and the B cell response to NC infection differed in DR1 and B10 mice. The response in B10 mice featured predominantly IFN-γ-secreting CD4 T cells and strong IgG2b/IgG2c production. In contrast, in DR1 mice most CD4 T cells secreted IL-2 and IgG production was IgG1-biased. Infection of DR1 mice with influenza PR8 generated a response that was comparable to that in B10 mice, with predominantly IFN-γ-secreting CD4 T cells and greater numbers of IgG2c than IgG1 antibody-secreting cells. The response to intramuscular vaccination with inactivated NC was similar in DR1 and B10 mice; the majority of CD4 T cells secreted IL-2 and most IgG antibody-secreting cells produced IgG2b or IgG2c. Our findings identify inherent host influences on characteristics of the virus-specific CD4 T cell and B cell responses that are restricted to the lung environment. Furthermore, we show that these host influences are substantially modulated by the type of infecting virus via the early induction of innate factors. Our findings emphasize the importance of immunization strategy for demonstrating inherent host differences in CD4 T cell and B cell responses.

Highlights

Studies of mouse models of influenza A virus infection have produced a comprehensive but as yet incomplete picture of disease pathogenesis and the innate and adaptive antiviral mechanisms that contribute to viral clearance and recovery
CD4 T cells purified from the mediastinal lymph node (MedLN) and spleen on day 10 after NC infection of DR1 transgenic (DR1) mice were tested for their ability to secrete IL-2, IFN-c, or IL-4 after stimulation with defined peptide epitopes
We conducted a similar analysis in B10 mice, a conventional mouse strain in which we had analyzed the response to NC infection and defined CD4 T cell-recognized epitopes in same set of viral proteins analyzed in DR1 mice [21]

Summary

Introduction

Studies of mouse models of influenza A virus infection have produced a comprehensive but as yet incomplete picture of disease pathogenesis and the innate and adaptive antiviral mechanisms that contribute to viral clearance and recovery. Optimal virus-specific Ab production by B cells following influenza infection is dependent on CD4 T cell help. After cognate interactions of peptide:MHC class II (MHC II)-bearing B cells with CD4 T cells, activated B cells may differentiate via the extrafollicular pathway to rapidly generate a population of short-lived virus-specific Ab-secreting cells (ASCs), or they may enter B cell follicles and initiate germinal center (GC) reactions where long-lasting populations of ASCs and memory B cells expressing high affinity antiviral Abs are formed [7]. A Th1-type cytokine profile fits well with the typical influenza-specific B cell response, which includes a predominance of the IgG2a (IgG2c in some mouse strains) and IgG2b isotypes. IFN-c promotes the expression of IgG2a/IgG2c and IgG2b by B cells [11,12]

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Conclusion