Abstract
CD4 is a coreceptor on T helper (Th) cells that interacts with MHC class II molecules (MHCII). The mechanisms mediating the effects of CD4 on responses by T helper cells to stimulation of the antigen-specific T cell receptor (TCR) are still poorly understood. Here, we demonstrate T cell costimulation via CD4 signalling independent of T cell receptor-mediated signals. Incubation of T helper cells with peptide mimetics of the CD4-binding region on the MHC class II beta2 domain caused intracellular calcium mobilization in the absence of antigen or other T cell receptor stimuli. Engagement of CD4 by peptide mimetics or wild-type MHC class II, but not by mutant MHC class II molecules incapable of engaging CD4, inhibited the T cell receptor-mediated increase in cyclic AMP (cAMP) concentrations in T helper cells. CD4-mediated signals activated cyclic AMP phosphodiesterases (PDEs) and inhibited adenylyl cyclase. Full activation and clonal expansion of antigen-stimulated T helper cells required the CD4-mediated regulation of cyclic AMP. Our results suggest a costimulatory mechanism of CD4 function that acts on the second messengers, calcium and cyclic AMP.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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2',3'-Cyclic-Nucleotide Phosphodiesterases / metabolism
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Adenylyl Cyclases / metabolism
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Animals
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CD4 Antigens / immunology*
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CD4 Antigens / metabolism
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Calcium Signaling / drug effects
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Calcium Signaling / immunology*
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Cell Communication / drug effects
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Cell Communication / immunology
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Cell Membrane / drug effects
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Cells, Cultured
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Cyclic AMP / metabolism*
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / immunology*
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Histocompatibility Antigens Class II / metabolism
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Interleukin-2 / biosynthesis
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Intracellular Fluid / metabolism
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Mice
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Mice, Transgenic
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Molecular Mimicry / immunology
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Mutation / genetics
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Peptides / pharmacology
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Protein Structure, Tertiary / physiology
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Receptors, Antigen, T-Cell / immunology
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T-Lymphocytes, Helper-Inducer / drug effects
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / metabolism
Substances
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CD4 Antigens
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Histocompatibility Antigens Class II
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Interleukin-2
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Peptides
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Receptors, Antigen, T-Cell
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Cyclic AMP
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2',3'-Cyclic-Nucleotide Phosphodiesterases
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Adenylyl Cyclases