title: IL-21 promotes late activator APC-mediated T follicular helper cell differentiation in experimental pulmonary virus infection.
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.
authors.affiliation: Inflammation Research, Amgen Inc., Seattle, Washington, United States of America; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Jae-Kwang
authors.initials: JK
authors.lastname: Yoo
authors.affiliation: Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America; Department of Microbiology, University of Virginia, Charlottesville, Virginia, United States of America; Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Braciale
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054370:Chemokine CXCL9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology / Q000502:physiology; D053738:Interleukin-21 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008171:Lung Diseases / Q000235:genetics / Q000276:immunology* / Q000821:virology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D054370:Chemokine CXCL9; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D054367:Receptors, CXCR3; D014409:Tumor Necrosis Factor-alpha; D000098546:Interleukin-21