Abstract
Background:
SH3 containing Lymphocyte Protein (SLY1) is a putative adapter protein exclusively expressed in lymphocytes which is involved in antigen receptor induced activation. We previously have generated SLY1Delta/Delta mice harbouring a partial deletion in the N-terminal region of SLY1 which revealed profound immunological defects in T and B cell functions.
Results:
In this study, T cell development in SLY1-/- and SLY1Delta/Delta mice was analysed ex vivo and upon cultivation with the bone marrow stromal cell line OP9. SLY1-deficient thymocytes were compromised in inducing nutrient receptor expression and ribosomal protein S6 phosphorylation, indicating a defect in mTOR complex activation. Furthermore, SLY1 was identified as a novel anti-apoptotic protein required for developmental progression of T cell precursors to the CD4+CD8+ double-positive stage by protecting from premature programmed cell death initiation in developing CD4-CD8- double-negative thymocytes. In addition, SLY1 phosphorylation was differentially regulated upon Notch ligand-mediated stimulation and expression of the preTCR.
Conclusion:
Thus, our results suggest a non-redundant role for SLY1 in integrating signals from both receptors in early T cell progenitors in the thymus.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / immunology
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Adaptor Proteins, Signal Transducing / metabolism*
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Adaptor Proteins, Vesicular Transport
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Animals
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Apoptosis
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CD4 Antigens
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CD8 Antigens
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Cell Differentiation
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Cell Line
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Gene Expression Regulation, Developmental
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / immunology
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Inhibitor of Apoptosis Proteins / metabolism*
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Lymphocyte Activation
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Membrane Glycoproteins / immunology
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Precursor Cells, T-Lymphoid / cytology
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Precursor Cells, T-Lymphoid / immunology
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Precursor Cells, T-Lymphoid / metabolism*
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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Receptors, Antigen, T-Cell, alpha-beta / immunology
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Receptors, Antigen, T-Cell, alpha-beta / metabolism*
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Receptors, Notch / immunology
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Receptors, Notch / metabolism
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Signal Transduction / immunology
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Thymus Gland / cytology
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Thymus Gland / growth & development
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Thymus Gland / immunology*
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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CD4 Antigens
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CD8 Antigens
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Inhibitor of Apoptosis Proteins
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Membrane Glycoproteins
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Receptors, Antigen, T-Cell
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Notch
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SLY1 protein, mouse
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pre-T cell receptor alpha