Abstract
The primary manifestation of X-linked lymphoproliferative syndrome, caused by a dysfunctional adapter protein, signaling lymphocyte activation molecule-associated protein (SAP), is an excessive T cell response upon EBV infection. Using the SAP-/- mouse as a model system for the human disease, we compared the response of CD8+ T cells from wild-type (wt) and mutant mice to various stimuli. First, we observed that CD8+ T cells from SAP-/- mice proliferate more vigorously than those from wt mice upon CD3/CD28 cross-linking in vitro. Second, we analyzed the consequence of SAP deficiency on CTL effector function and homeostasis. For this purpose, SAP-/- and wt mice were infected with the murine gamma-herpesvirus 68 (MHV-68). At 2 wk postinfection, the level of viral-specific CTL was much higher in mutant than in wt mice, measured both ex vivo and in vivo. In addition, we established that throughout 45 days of MHV-68 infection the frequency of virus-specific CD8+ T cells producing IFN-gamma was significantly higher in SAP-/- mice. Consequently, the level of latent infection by MHV-68 was considerably lower in SAP-/- mice, which indicates that SAP-/- CTL control this infection more efficiently than wt CTL. Finally, we found that the Vbeta4-specific CD8+ T cell expansion triggered by MHV-68 infection is also enhanced and prolonged in SAP-/- mice. Taken together, our data indicate that SAP functions as a negative regulator of CD8+ T cell activation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, CD
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BALB 3T3 Cells
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CD28 Antigens / immunology
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CD28 Antigens / metabolism
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CD3 Complex / immunology
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CD3 Complex / metabolism
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / virology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Line, Tumor
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Cell Proliferation
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Cross-Linking Reagents / metabolism
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Cytotoxicity, Immunologic / genetics
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Down-Regulation / immunology*
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Epitopes, T-Lymphocyte / immunology
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Gammaherpesvirinae / immunology
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Glycoproteins / metabolism*
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Herpesviridae Infections / genetics
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Herpesviridae Infections / immunology
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Immunoglobulins / metabolism*
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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 Activation / genetics
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Lymphocyte Activation / immunology
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Lymphocyte Count
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Cell Surface
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Signal Transduction / immunology*
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Signaling Lymphocytic Activation Molecule Associated Protein
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Signaling Lymphocytic Activation Molecule Family Member 1
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Spleen / cytology
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Spleen / immunology
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Spleen / virology
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Virus Latency / immunology
Substances
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Antigens, CD
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CD28 Antigens
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CD3 Complex
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Cross-Linking Reagents
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Epitopes, T-Lymphocyte
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Glycoproteins
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Immunoglobulins
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Intracellular Signaling Peptides and Proteins
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Cell Surface
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Sh2d1a protein, mouse
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Signaling Lymphocytic Activation Molecule Associated Protein
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Signaling Lymphocytic Activation Molecule Family Member 1