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Signaling Lymphocyte Activation Molecule-Associated Protein Is a Negative Regulator of the CD8 T Cell Response in Mice¹

Gang Chen^2,*, Albert K. Tai^2,*, Miao Lin^*, Francesca Chang^*, Cox Terhorst and Brigitte T. Huber^3,*

^* Department of Pathology, Tufts University School of Medicine, Boston, MA 02111; and Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

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 -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- 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 V4-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.

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