Abstract
IL-21 is a type-I cytokine that has pleiotropic immuno-modulatory effects. Primarily produced by activated T cells including NKT and TFH cells, IL-21 plays a pivotal role in promoting TFH differentiation through poorly understood cellular and molecular mechanisms. Here, employing a mouse model of influenza A virus (IAV) infection, we demonstrate that IL-21, initially produced by NKT cells, promotes TFH differentiation by promoting the migration of late activator antigen presenting cell (LAPC), a recently identified TFH inducer, from the infected lungs into the draining lymph nodes (dLN). LAPC migration from IAV-infected lung into the dLN is CXCR3-CXCL9 dependent. IL-21-induced TNF-α production by conventional T cells is critical to stimulate CXCL9 expression by DCs in the dLN, which supports LAPC migration into the dLN and ultimately facilitates TFH differentiation. Our results reveal a previously unappreciated mechanism for IL-21 modulation of TFH responses during respiratory virus infection.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen-Presenting Cells / immunology*
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Antigen-Presenting Cells / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cell Movement / genetics
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Cell Movement / immunology
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Chemokine CXCL9 / genetics
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Chemokine CXCL9 / immunology
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Chemokine CXCL9 / metabolism
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Flow Cytometry
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Host-Pathogen Interactions / immunology
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Influenza A virus / immunology
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Influenza A virus / physiology
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Interleukin-21 Receptor alpha Subunit / deficiency
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Interleukin-21 Receptor alpha Subunit / genetics
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Interleukin-21 Receptor alpha Subunit / immunology
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Interleukins / deficiency
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Interleukins / genetics
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Interleukins / immunology*
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Lung Diseases / genetics
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Lung Diseases / immunology*
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Lung Diseases / virology
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Mice, Inbred C57BL
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Mice, Knockout
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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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Receptors, CXCR3 / genetics
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Receptors, CXCR3 / immunology
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Receptors, CXCR3 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / metabolism
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Tumor Necrosis Factor-alpha / deficiency
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
Substances
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Chemokine CXCL9
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Cxcl9 protein, mouse
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Cxcr3 protein, mouse
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Interleukin-21 Receptor alpha Subunit
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Interleukins
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Receptors, CXCR3
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Tumor Necrosis Factor-alpha
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interleukin-21