Signaling lymphocyte activation molecule-associated protein is a negative regulator of the CD8 T cell response in mice.
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.
Chen
Gang
G
Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
Tai
Albert K
AK
Lin
Miao
M
Chang
Francesca
F
Terhorst
Cox
C
Huber
Brigitte T
BT
D000818:Animals; D015703:Antigens, CD; D041702:BALB 3T3 Cells; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003432:Cross-Linking Reagents / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D018142:Gammaherpesvirinae / Q000276:immunology; D006023:Glycoproteins / Q000378:metabolism*; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology; D007136:Immunoglobulins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000276:immunology*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000821:virology; D017735:Virus Latency / Q000276:immunology
D015703:Antigens, CD; D018106:CD28 Antigens; D017252:CD3 Complex; D003432:Cross-Linking Reagents; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011956:Receptors, Cell Surface; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1