Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

Abstract

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 TCRinduced 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. IntroductionX-linked lymphoproliferative syndrome (XLP), an abnormal immune response to EBV infection characterized by fatal infectious mononucleosis, dys-gammaglobulinemia and B cell lymphoma, is caused by mutations in the SH2D1A gene, which encodes signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) [1][2][3][4]. The adaptor SAP binds with high affinity to tyrosine motifs in the cytoplasmic domain of SLAM family immune receptors, including SLAM (CD150), CD244, CD229, SLAMF6, SLAMF7 and CD84, suggesting that SAP functions are important in modulating signals initiated by the SLAM family receptors [5][6][7][8]. It has been well established that SAP is an essential adaptor due to its capacity to recruit FynT to SLAM and p85 of PI3 K to 2B4, respectively [9,10]. SAP is expressed in activated T, NK and NKT cells, as well as in germinal center B cells [11,12], and is indispensable for normal NKT cell development, generation of a proper Th2 response and Ig class switching in humans and mice [13][14][15][16][17][18]. In XLP patients, both EBV-infected B cells and EBVspecific CTL hyper-proliferate, although the underlying mechanism is still controversial. Previous studies with SAP -/-mice, performed by several laboratories including ours, showed an increased antigen-specific CD8 + T cell population and IFN-c production after infection with lymphocytic choriomeningitis virus (LCMV), murine c-herpesvirus 68 (MHV-68) and Toxoplasma gondii, but impaired Th2 cell differentiation and decreased IgG production [15,19,20]. In addition, we demonstrate that SAP -/-mice confer greater cytotoxic activity and increased proliferation of CD8 + T cells compared to WT mice, strongly suggesting that SAP fine-tunes th...

Breakdown in Repression of IFN-γ mRNA Leads to Accumulation of Self-Reactive Effector CD8+ T Cells

“…These can cause immunopathology if they are recruited into antiviral responses and fail to contract postinfection. In addition to T cell anergy, activation-induced cell death and the proapoptotic molecule Bim keep autoreactive CD8 + T cells in check (19)(20)(21). Extrinsic mechanisms also operate to repress self-reactive T cells; these include availability of cytokines, such as IL-7 and IL-15 (22,23), and the suppressive effect of regulatory T cells through their ability to secrete IL-10 and TGF-b (24).…”

Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency

“…Chen et al recently observed a survival advantage for SAP-knockout murine CD8 + T cells 48 hours after primary stimulation, which they characterized as a defect in activation-induced cell death (AICD) (21). As Strasser and colleagues recently pointed out, the term "AICD" is broadly used to refer to any form of lymphocyte death after antigen stimulation and does not distinguish between the possible mechanisms of lymphocyte apoptosis described above (22).…”

The apoptosis modulating role of SAP (SLAM associated protein) contributes to the symptomatology of the X linked lymphoproliferative disease

“…Indeed, p73 deficiency was detected in SAP negative mouse T cells and this was connected with impairment of activation induced cell death. 42 The postulated scenario is shown in Figure 2: SAP expressed at high levels in the late phases of T cell activation binds VCP. In this state the VCP activity may be impaired and therefore it does not elevate NFκB activity.…”