Abstract
Follicular helper T cells (T(FH) cells) provide critical help to B cells during humoral immune responses. Here we report that mice with T cell-specific deletion of the miR-17∼92 family of microRNAs (miRNAs) had substantially compromised T(FH) differentiation, germinal-center formation and antibody responses and failed to control chronic viral infection. Conversely, mice with T cell-specific expression of a transgene encoding miR-17∼92 spontaneously accumulated T(FH) cells and developed a fatal immunopathology. Mechanistically, the miR-17∼92 family controlled the migration of CD4(+) T cells into B cell follicles by regulating signaling intensity from the inducible costimulator ICOS and kinase PI(3)K by suppressing expression of the phosphatase PHLPP2. Our findings demonstrate an essential role for the miR-17∼92 family in T(FH) differentiation and establish PHLPP2 as an important mediator of their function in this process.
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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B-Lymphocytes / immunology*
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Cell Differentiation / immunology*
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Flow Cytometry
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Germinal Center / cytology
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Germinal Center / immunology*
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Immunity, Humoral / immunology
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Immunohistochemistry
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Inducible T-Cell Co-Stimulator Protein / immunology
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Lymphocytic Choriomeningitis / immunology
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Lymphocytic Choriomeningitis / virology
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Lymphocytic choriomeningitis virus / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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MicroRNAs / immunology*
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Nuclear Proteins / immunology*
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Phosphatidylinositol 3-Kinases / immunology
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Phosphoprotein Phosphatases / immunology*
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Signal Transduction / immunology
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Specific Pathogen-Free Organisms
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T-Lymphocytes, Helper-Inducer / cytology
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T-Lymphocytes, Helper-Inducer / enzymology
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T-Lymphocytes, Helper-Inducer / immunology*
Substances
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Icos protein, mouse
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Inducible T-Cell Co-Stimulator Protein
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MIRN17-92 microRNA, mouse
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MicroRNAs
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Nuclear Proteins
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PHLPP1 protein, mouse
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Phosphoprotein Phosphatases