Abstract
Humans and mice deficient in the adaptor protein SAP (Sh2d1a) have a major defect in humoral immunity, resulting from a lack of T cell help for B cells. The role of SAP in this process is incompletely understood. We found that deletion of receptor Ly108 (Slamf6) in CD4(+) T cells reversed the Sh2d1a(-/-) phenotype, eliminating the SAP requirement for germinal centers. This potent negative signaling by Ly108 required immunotyrosine switch motifs (ITSMs) and SHP-1 recruitment, resulting in high amounts of SHP-1 at the T cell:B cell synapse, limiting T cell:B cell adhesion. Ly108-negative signaling was important not only in CD4(+) T cells; we found that NKT cell differentiation was substantially restored in Slamf6(-/-)Sh2d1a(-/-) mice. The ability of SAP to regulate both positive and negative signals in T cells can explain the severity of SAP deficiency and highlights the importance of SAP and SHP-1 competition for Ly108 ITSM binding as a rheostat for the magnitude of T cell help to B cells.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Animals
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Antigens, Ly / genetics
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Antigens, Ly / physiology*
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B-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / immunology*
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Germinal Center / immunology
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Immunologic Deficiency Syndromes / genetics
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Immunologic Deficiency Syndromes / immunology
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Immunological Synapses / immunology
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Inositol Polyphosphate 5-Phosphatases
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Intracellular Signaling Peptides and Proteins / deficiency
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / physiology
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Lymphocyte Cooperation / physiology*
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Lymphopoiesis / physiology*
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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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Natural Killer T-Cells / cytology*
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Phosphoric Monoester Hydrolases / physiology
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Phosphorylation
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Phosphotyrosine / physiology
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Protein Processing, Post-Translational
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Signaling Lymphocytic Activation Molecule Associated Protein
Substances
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Antigens, Ly
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Intracellular Signaling Peptides and Proteins
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Ly108 protein, mouse
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Sh2d1a protein, mouse
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Signaling Lymphocytic Activation Molecule Associated Protein
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Phosphotyrosine
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Phosphoric Monoester Hydrolases
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Inositol Polyphosphate 5-Phosphatases