Abstract
B cells are required for follicular Th (Tfh) cell development, as is the ICOS ligand (ICOS-L); however, the separable contributions of Ag and ICOS-L delivery by cognate B cells to Tfh cell development and function are unknown. We find that Tfh cell and germinal center differentiation are dependent on cognate B cell display of ICOS-L, but only when Ag presentation by the latter is limiting, with the requirement for B cell expression of ICOS-L overcome by robust Ag delivery. These findings demonstrate that Ag-specific B cells provide different, yet compensatory, signals for Tfh cell differentiation, while reconciling conflicting data indicating a requirement for ICOS-L expression on cognate B cells for Tfh cell development with those demonstrating that the latter requirement could be bypassed in lieu of that tendered by noncognate B cells. Our findings clarify the separable roles of delivery of Ag and ICOS-L by cognate B cells for Tfh cell maturation and function, and have implications for using therapeutic ICOS blockade in settings of abundantly available Ag, such as in systemic autoimmunity.
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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Antigens / immunology*
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Antigens, CD19 / genetics
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Antigens, CD19 / immunology
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Antigens, CD19 / metabolism
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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Cell Proliferation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Flow Cytometry
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Inducible T-Cell Co-Stimulator Ligand / genetics
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Inducible T-Cell Co-Stimulator Ligand / immunology*
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Inducible T-Cell Co-Stimulator Ligand / metabolism
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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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Microscopy, Confocal
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Nitrophenols / immunology
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Ovalbumin / immunology
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Phenylacetates / immunology
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Proto-Oncogene Proteins c-bcl-6
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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
Substances
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Antigens
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Antigens, CD19
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Bcl6 protein, mouse
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DNA-Binding Proteins
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Icosl protein, mouse
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Inducible T-Cell Co-Stimulator Ligand
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Nitrophenols
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Phenylacetates
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Proto-Oncogene Proteins c-bcl-6
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4-hydroxy-5-nitrophenyl acetic acid
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Ovalbumin