Increased proliferation of CD8+ T cells in SAP-deficient mice is associated with impaired activation-induced cell death.
Defective signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is responsible for the human X-linked lymphoproliferative syndrome. Defects in T helper 2, natural killer, natural killer T and B cells have been demonstrated in SAP-deficient humans and mice, and increased proliferation of CD8+ T cells has been observed. In the current study, we investigated the properties of CD8+ T cell proliferation and activation-induced cell death (AICD), using OT-I T cell receptor (TCR)-transgenic mice on either wild-type (WT) or SAP-/- background. Interestingly, we found that ovalbumin peptide-activated SAP-/- CD8+ T cells have lower AICD compared to their WT counterparts. Furthermore, the induction of p73, a key mediator of TCR-induced apoptosis through the mitochondrial apoptotic pathway, was significantly reduced at both the mRNA and protein levels in the activated mutant cells. Meanwhile, a reduced level of activated caspase 9 was observed in the mutant cells. We conclude that reduced AICD in activated SAP-/- CD8+ T cells is associated with impaired p73 induction, indicating that the initiation of the mitochondrial apoptotic pathway might be impaired. Our data demonstrate an intrinsic defect in SAP-/- CD8+ T cells and shed light on the increased responsiveness of CD8+ T cells in SAP-/- mice.
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; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein
D047908:Intracellular Signaling Peptides and Proteins; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein