Abstract
Costimulatory signals are critical to T cell activation, but how their effects are mediated remains incompletely characterized. Here, we demonstrate that locally produced C5a and C3a anaphylatoxins interacting with their G protein-coupled receptors (GPCRs), C5aR and C3aR, on APCs and T cells both upstream and downstream of CD28 and CD40L signaling are integrally involved in T cell proliferation and differentiation. Disabling these interactions reduced MHC class II and costimulatory-molecule expression and dramatically diminished T cell responses. Importantly, impaired T cell activation by Cd80-/-Cd86-/- and Cd40-/- APCs was reconstituted by added C5a or C3a. C5aR and C3aR mediated their effects via PI-3 kinase-gamma-dependent AKT phosphorylation, providing a link between GPCR signaling, CD28 costimulation, and T cell survival. These local paracrine and autocrine interactions thus operate constitutively in naive T cells to maintain viability, and their amplification by cognate APC partners thus is critical to T cell costimulation.
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 Presentation / immunology
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Antigen-Presenting Cells / immunology
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B7-1 Antigen / immunology
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B7-1 Antigen / metabolism
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CD28 Antigens / immunology
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CD28 Antigens / metabolism
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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CD40 Antigens / immunology
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CD40 Antigens / metabolism
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CD40 Ligand / immunology
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CD40 Ligand / metabolism
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Cell Differentiation / immunology
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Cell Survival / immunology*
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Complement C3a / immunology*
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Complement C3a / metabolism
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Complement C5a / immunology*
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Complement C5a / metabolism
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Flow Cytometry
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Immunoblotting
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Immunoprecipitation
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Lymphocyte Activation / immunology*
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Mice
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Mice, Transgenic
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Polymerase Chain Reaction
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RNA, Messenger / analysis
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Receptor, Anaphylatoxin C5a / immunology
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Receptor, Anaphylatoxin C5a / metabolism
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Signal Transduction / immunology
Substances
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B7-1 Antigen
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CD28 Antigens
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CD40 Antigens
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RNA, Messenger
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Receptor, Anaphylatoxin C5a
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CD40 Ligand
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Complement C3a
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Complement C5a