T Cell Division and Death Are Segregated by Mutation of TCRβ Chain Constant Domains

Teixeiro, Emma; Daniëls, Mark A.; Hausmann, Barbara; Schrum, Adam G.; Naeher, Dieter; Luescher, Immanuel F.; Thome, Margot; Bragado, Rafael; Palmer, Ed

doi:10.1016/j.immuni.2004.08.014

Cited by 40 publications

(31 citation statements)

References 48 publications

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“…Furthermore, full-length p73a is the major isoform induced by TCR signaling and is required for apoptosis of activated T cells [25,28,36]. Thus, we proceeded to investigate the induction of p73 in activated SAP -/-OT-I cells, in order to elucidate the cause of reduced cell death in these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Two transcription factors, E2F-1 and p73, are indispensable for the induction of AICD of T cells through this pathway, since primary T cells lacking either of these proteins are resistant to TCR-mediated apoptosis [25][26][27]. In addition, decreased levels of E2F-1 and p73 expression have been shown to be responsible for defective AICD in T cells carrying a mutation in the transmembrane region of the TCR b chain [28]. Within this pathway, Bcl-2 and Bcl-xL have anti-apoptotic function through the stabilization of the mitochondrial membrane potential.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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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...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…An implication of this finding was that proliferating T cells frequently die during proliferation unless TLR agonists are present to prevent cell loss. Although several studies have measured T cell death during division in culture models of clonal expansion [13][14][15] it is not possible to do similar studies in intact animals due to rapid phagocytosis of dead or dying T cells [16]. Even in the thymus, in which approximately 98% of developing T cells are destined to die, it is only possible to detect apoptotic remnants of cells with great difficulty [17].…”

Section: Introductionmentioning

confidence: 99%

Peptide-stimulated DO11.10 T cells divide well but accumulate poorly in the absence of TLR agonist treatment

et al. 2005

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Immunological adjuvants increase the clonal burst size of antigen-specific T cell populations by mechanisms that remain incompletely understood. Using the DO11.10 adoptive transfer system to study peptide-stimulated T cell responses, we found that TLR agonist treatment increased the extent of cellular division undergone by responding T cells, but not by enough to explain the net increases in T cell yield that were achieved. Two novel analyses involving CFSE dye dilution analysis were used to characterize the shortfall, both of which were consistent with the idea that DO11.10 T cells are frequently lost during proliferation unless TLR agonists are present. T cell loss during clonal expansion was correlated with decreased levels of Bcl-2, but TLR agonists did not appear to afford protection by restoring levels of Bcl-2 or of cell surface IL-7Ra chain expression. TLR-mediated protection also failed to correlate with increased expression of Bcl-x or decreased expression of pro-apoptotic Bim. Our findings suggest that DO11.10 T cells stimulated by antigenic peptide in vivo divide well, but fail to accumulate efficiently unless TLR agonists are present.

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“…Indeed, it has been reported that a mutant of the transmembrane and cytoplasmic domains of the TCRb chain is impaired in recruiting Carma1 and Bcl10 and consequently in activating NF-kB. 67 In addition to being important for the recruitment of Bcl10 to the IS, Carma1 may also be important for the recruitment of PKCy. 66 However, another study did not reach the same conclusion but rather concluded that recruitment of PKCy to central and peripheral IS occurred normally in Carma1 deficient T cells.…”

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confidence: 99%

Deciphering the pathway from the TCR to NF-κB

Weil

Israël

2006

Cell Death Differ

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A major regulator of lymphocyte survival and activation is the transcription factor nuclear factor-jB (NF-jB). Controlled activation of NF-jB is essential for the immune and inflammatory response as well as for cell proliferation and protection against apoptosis. The NEMO/IjB kinase (IKK) complex is the central integrator of most stimuli leading to NF-jB activation, but a detailed knowledge of the upstream events is available only for a limited number of stimuli. In particular, although most players have probably been identified, relatively little is known about the detailed molecular mechanisms involved in the cascade leading to NF-jB activation following engagement of the T-cell receptor by a foreign antigen. In this review, we discuss recent insights into this specific signal transduction cascade, and the way it is controlled both spatially and temporally.

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T Cell Division and Death Are Segregated by Mutation of TCRβ Chain Constant Domains

Cited by 40 publications

References 48 publications

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

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

Peptide-stimulated DO11.10 T cells divide well but accumulate poorly in the absence of TLR agonist treatment

Deciphering the pathway from the TCR to NF-κB

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T Cell Division and Death Are Segregated by Mutation of TCRβ Chain Constant Domains

Cited by 40 publications

References 48 publications

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

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

Peptide-stimulated DO11.10 T cells divide well but accumulate poorly in the absence of TLR agonist treatment

Deciphering the pathway from the TCR to NF-κB

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Product

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

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