Abstract
A strong humoral response to infection requires the collaboration of several hematopoietic cell types that communicate via antigen presentation, surface coreceptors and their ligands, and secreted factors. The proinflammatory cytokine IL-6 has been shown to promote the differentiation of activated CD4(+) T cells into T follicular helper cells (T(FH) cells) during an immune response. T(FH) cells collaborate with B cells in the formation of germinal centers (GCs) during T cell-dependent antibody responses, in part through secretion of critical cytokines such as IL-21. In this study, we demonstrate that loss of either IL-6 or IL-21 has marginal effects on the generation of T(FH) cells and on the formation of GCs during the response to acute viral infection. However, mice lacking both IL-6 and IL-21 were unable to generate a robust T(FH) cell-dependent immune response. We found that IL-6 production in follicular B cells in the draining lymph node was an important early event during the antiviral response and that B cell-derived IL-6 was necessary and sufficient to induce IL-21 from CD4(+) T cells in vitro and to support T(FH) cell development in vivo. Finally, the transcriptional activator Oct2 and its cofactor OBF-1 were identified as regulators of Il6 expression in B cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Viral / immunology
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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Blotting, Western
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Flow Cytometry
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Gene Expression Regulation / immunology
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Germinal Center / immunology
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Germinal Center / metabolism
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Germinal Center / virology
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Host-Pathogen Interactions / immunology
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Influenza A Virus, H3N2 Subtype / immunology
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Influenza A Virus, H3N2 Subtype / physiology
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Interleukin-6 / deficiency
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Interleukin-6 / genetics
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Interleukin-6 / immunology*
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Interleukins / genetics
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Interleukins / immunology*
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Interleukins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Octamer Transcription Factor-2 / genetics
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Octamer Transcription Factor-2 / immunology*
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Octamer Transcription Factor-2 / metabolism
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Orthomyxoviridae Infections / genetics
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Orthomyxoviridae Infections / immunology
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Orthomyxoviridae Infections / virology
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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T-Lymphocytes, Helper-Inducer / immunology
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T-Lymphocytes, Helper-Inducer / metabolism
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Trans-Activators / genetics
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Trans-Activators / immunology*
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Trans-Activators / metabolism
Substances
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Antibodies, Viral
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Interleukin-6
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Interleukins
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Octamer Transcription Factor-2
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Pou2af1 protein, mouse
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Pou2f2 protein, mouse
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Trans-Activators
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interleukin-21