Abstract
T cell help to B cells is a fundamental property of adaptive immunity, yet only recently have many of the cellular and molecular mechanisms of T cell help emerged. T follicular helper (Tfh) cells are the CD4(+) T helper cells that provide cognate help to B cells for high-affinity antibody production in germinal centers (GC). Tfh cells produce interleukin-21 (IL-21), and we show that IL-21 was necessary for GC formation. However, the central role of IL-21 in GC formation reflected its effects on Tfh cell generation rather than on B cells. Expression of the inducible costimulator (ICOS) was necessary for optimal production of IL-21, indicative of interplay between these two Tfh cell-expressed molecules. Finally, we demonstrate that IL-21's costimulatory capacity for T helper cell differentiation operated at the level of the T cell receptor signalosome through Vav1, a signaling molecule that controls T cell helper function. This study reveals a previously unappreciated role for Tfh cells in the formation of the GC and isotype switching through a CD4(+) T cell-intrinsic requirement for IL-21.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Differentiation, T-Lymphocyte / immunology
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Antigens, Differentiation, T-Lymphocyte / metabolism
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B-Lymphocytes / cytology
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B-Lymphocytes / immunology
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Blotting, Western
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Cell Differentiation / immunology
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Electrophoresis, Polyacrylamide Gel
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Germinal Center / cytology*
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Germinal Center / immunology
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Immunoglobulin Class Switching / immunology
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Immunohistochemistry
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Inducible T-Cell Co-Stimulator Protein
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Interleukins / immunology*
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Interleukins / metabolism
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Lymphocyte Activation / immunology
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Lymphocyte Cooperation / immunology*
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Mice
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Microscopy, Confocal
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Proto-Oncogene Proteins c-vav / immunology
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Proto-Oncogene Proteins c-vav / metabolism
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T-Lymphocyte Subsets / cytology*
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T-Lymphocyte Subsets / immunology
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T-Lymphocytes, Helper-Inducer / cytology*
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T-Lymphocytes, Helper-Inducer / immunology
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Transfection
Substances
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Antigens, Differentiation, T-Lymphocyte
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Icos protein, mouse
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Inducible T-Cell Co-Stimulator Protein
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Interleukins
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Proto-Oncogene Proteins c-vav
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Vav1 protein, mouse
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interleukin-21