Activation‐induced cell death in T cells

Green, Douglas R.; Droin, Nathalie; Pinkoski, Michael J.

doi:10.1034/j.1600-065x.2003.00051.x

Cited by 533 publications

(453 citation statements)

References 123 publications

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“…It serves as a death factor during immune response termination by AICD 31 and for the establishment of immune privileged tissues. 32 Genetic defects of Fas/FasL-associated apoptosis pathways lead to autoimmune lymphoproliferative syndromes in mice and humans.…”

Section: Discussionmentioning

confidence: 99%

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

et al. 2007

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The apoptosis-inducing Fas ligand (FasL) is a type II transmembrane protein that is involved in the downregulation of immune reactions by activation-induced cell death (AICD) as well as in T cell-mediated cytotoxicity. Proteolytic cleavage leads to the generation of membrane-bound N-terminal fragments and a soluble FasL (sFasL) ectodomain. sFasL can be detected in the serum of patients with dysregulated inflammatory diseases and is discussed to affect Fas-FasL-mediated apoptosis. Using pharmacological approaches in 293T cells, in vitro cleavage assays as well as loss and gain of function studies in murine embryonic fibroblasts (MEFs), we demonstrate that the disintegrin and metalloprotease ADAM10 is critically involved in the shedding of FasL. In primary human T cells, FasL shedding is significantly reduced after inhibition of ADAM10. The resulting elevated FasL surface expression is associated with increased killing capacity and an increase of T cells undergoing AICD. Overall, our findings suggest that ADAM10 represents an important molecular modulator of FasL-mediated cell death.

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Section: Discussionmentioning

confidence: 99%

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

et al. 2007

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“…However, a fraction of low-affinity self-reactive T cells may escape thymic negative selection [30], and thus, to avoid autoimmunity, a range of additional tolerogenic mechanisms are required in the periphery. Indeed, peripheral mechanisms such as anergy [31], peripheral deletion [32] or suppression by regulatory T cells [33] have been described. It was recently reported that the number and functionality of Aire -/-regulatory T cells were intact [28].…”

Section: Introductionmentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire -/-dendritic cells (DC) activate naive T cells more efficiently than do Aire +/+ DC. Expression array analyses of Aire -/-DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire -/-DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire -/-DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire -/-DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire -/-mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35240_s.pdf IntroductionInactivation of the autoimmune regulator gene (AIRE) [1][2][3] causes autoimmunity in patients with autoimmune polyendocrine syndrome type I (APS I, APECED, OMIM 240300) and in a gene targeted mouse model [4,5]. APS I is a rare monogenic autosomal recessive disease without HLA association [6,7], which is prevalent in isolated populations [8][9][10]. APS I patients develop a progressive loss of tolerance against self antigens and suffer from multiorgan failures due to the immunological destruction of adrenals, parathyroid glands and b cells of the islets of Langerhans [11]. Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14]. Functional studies of AIRE suggest a role as a transcription factor and in vitro transactivating studies support this notion [15][16][17][18]. Moreover, the PHD1 domain of AIRE has been suggested to have an E3 ubiquitin ligase activity in cell-free assays [19], findings in variance with a recent report [20]. Aire is highly expressed in a subset of the medullary thymic epithelial cells (mTEC) as well as in DC in the spleen and lymph nodes [21][22][23][24], indicating a potential role in immunological tolerance.To characterize the function of Aire, we previously engineered an Aire-deficient mouse targeting the most common APS I mutation [4]. Aire-deficient mice develop multiple organ-specific autoantibodies and lymphocytic infiltrates, thus mimicking some of the features of human APS I [4]. Subsequently, the role of Aire in negative selection was demonstrated [5]. These findings were further supported using TCR transgenic mic...

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“…Induction of FasL expression has been implicated in drug-and stress-induced apoptotic death of T lymphocytes. 7 Upon stimulation, Fas undergoes trimerization and recruits the proapoptotic adapter protein Fas-associated death domain (FADD) and pro-caspase-8, also called FADDlike interleukin 1 b-converting enzyme (FLICE), to form a death-inducing signaling complex (DISC). [8][9][10][11] Recruitment of pro-caspase-8 to the DISC leads to its proteolytic activation to caspase-8, followed by initiation of a caspase cascade leading to apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…17 In fact, the susceptibility of T lymphocytes to Fas-mediated apoptosis correlates with c-FLIP levels, which are elevated during the early stages of activation but are significantly reduced upon re-stimulation when the T cells undergo AICD. 7,18,19 The molecular mechanisms involved in the regulation of expression of c-FLIP in T lymphocytes are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

Akt inhibition upregulates FasL, downregulates c-FLIPs and induces caspase-8-dependent cell death in Jurkat T lymphocytes

Uriarte¹,

Joshi‐Barve²,

Song³

et al. 2005

Cell Death Differ

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In T lymphocytes, the role of Akt in regulating Fas/Fas ligand (FasL)-mediated apoptotic signaling and death is not clearly understood. In this study, we observed that inhibition of Akt causes enhanced expression of FasL mRNA and protein and increased death-inducing signaling complex (DISC) formation with Fas-associated death domain (FADD) and procaspase-8 recruitment. Also, caspase-8 was activated at the DISC with accompanying decrease in c-FLIP s expression. FasL neutralizing antibody significantly decreased apoptotic death in the Akt-inhibited T cells. Additionally, Akt inhibition-induced Fas signaling was observed to link to the mitochondrial pathway via Bid cleavage. Further, inhibition of caspase-8 activity effectively blocked the loss of mitochondrial membrane potential and DNA fragmentation, suggesting that DISC formation and subsequent caspase-8 activation are critical initiating events in Akt inhibition-induced apoptotic death in T lymphocytes. These data demonstrate yet another important survival function governed by Akt kinase in T lymphocytes, which involves the regulation of FasL expression and consequent apoptotic signaling.

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Activation‐induced cell death in T cells

Cited by 533 publications

References 123 publications

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Akt inhibition upregulates FasL, downregulates c-FLIPs and induces caspase-8-dependent cell death in Jurkat T lymphocytes

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