Abstract
Th17 lymphocytes play a key role during immune responses against bacteria and fungi and are involved in the pathophysiology of multiple autoimmune disorders. The co-stimulatory molecules SLAMF3 and SLAMF6 have been implicated in the formation of Th17 phenotypes and IL-17A expression. Increased surface expression of SLAMF3 and SLAMF6 has been linked with disease activity in systemic lupus erythematosus. Here we demonstrate that in human total T lymphocytes the canonical CD28 and the non-canonical SLAMF3/SLAMF6 co-stimulatory pathways cooperate in the recruitment of the transcription factor NFAT1 to the IL17A promoter. Furthermore, the dominance of the SLAMF3/SLAMF6 pathway in inducing IL-17A production can be attributed to an increased nuclear abundance and recruitment of RORγt to the IL17A promoter. Thus, we have identified an additional mechanism that may be central for the specific control of IL17A gene regulation in systemic lupus erythematosus T lymphocytes.
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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Antibodies / immunology
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Antibodies / pharmacology
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Antigens, CD / genetics
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Antigens, CD / immunology*
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Antigens, CD / metabolism
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CD28 Antigens / genetics
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CD28 Antigens / immunology
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CD28 Antigens / metabolism
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Cells, Cultured
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Chromatin Immunoprecipitation
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Gene Expression Regulation / drug effects
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Gene Knockdown Techniques
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Humans
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Immunoblotting
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Interleukin-17 / genetics
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Interleukin-17 / immunology
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Interleukin-17 / metabolism
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Lupus Erythematosus, Systemic / genetics
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Lupus Erythematosus, Systemic / immunology
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Lupus Erythematosus, Systemic / metabolism
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Mutation
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / immunology
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NFATC Transcription Factors / metabolism
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Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
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Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology*
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Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
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Promoter Regions, Genetic / genetics*
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Protein Binding
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Receptor-CD3 Complex, Antigen, T-Cell / genetics
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Receptor-CD3 Complex, Antigen, T-Cell / immunology*
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Receptor-CD3 Complex, Antigen, T-Cell / metabolism
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / immunology*
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Receptors, Cell Surface / metabolism
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Signaling Lymphocytic Activation Molecule Family
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Signaling Lymphocytic Activation Molecule Family Member 1
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
Substances
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Antibodies
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Antigens, CD
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CD28 Antigens
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Interleukin-17
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LY9 protein, human
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NFATC Transcription Factors
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NFATC2 protein, human
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Receptor-CD3 Complex, Antigen, T-Cell
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Receptors, Cell Surface
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SLAMF6 protein, human
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Signaling Lymphocytic Activation Molecule Family
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Signaling Lymphocytic Activation Molecule Family Member 1