Reactive Oxygen Species Regulate Activation-Induced T Cell Apoptosis

Hildeman, David A.; Mitchell, Tom; Teague, T. Kent; Henson, Peter M.; Day, Brian J.; Kappler, John W.; Marrack, Philippa

doi:10.1016/s1074-7613(00)80072-2

Cited by 452 publications

(389 citation statements)

References 53 publications

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“…We have also found previously that FasL and APO2L/TRAIL are stored inside normal human T cell blasts in cytoplasmic compartments with characteristics of multivesicular bodies [14] and that they are rapidly released into the supernatant in their bioactive form associated with the internal microvesicles upon reactivation [14,15]. However, death receptor-independent mechanisms are also implicated in AICD, such as the generation of free radicals after TCR engagement and/or Bim-dependent processes [16,17].In a recent study, we have observed that in the presence of IL-2, cytotoxic anti-Fas mAb, recombinant APO2L/TRAIL (rApo2L), or supernatants from T cell blasts pulse-stimulated with PHA or through CD3 or CD59 ligation and containing bioactive FasL and/or APO2L/TRAIL on microvesicles induced rather inhibition of IL-2-dependent growth and not cell death of normal human T cell blasts. Cell death was only observed in the presence of cycloheximide (CHX) or after a pulse through CD3 or CD59, correlating in both cases with a net reduction in c-FLIP L and c-FLIP S expression [18].…”

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confidence: 60%

Human CD8+ T cell blasts are more sensitive than CD4+ T cell blasts to regulation by APO2L/TRAIL

et al. 2005

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The mechanisms responsible for the down-modulation of the activation of separated CD4 + or CD8 + human T cell blasts were studied using cells obtained from healthy donors. In the presence of IL-2, human CD8 + T cell blasts were more sensitive than CD4 + T cell blasts to regulation by APO2 ligand/TNF-related apoptosis-inducing ligand (APO2L/TRAIL), while both T cell subsets were equally sensitive to Fas/CD95 regulation. This regulation was defined as inhibition of IL-2-dependent T cell growth in the absence of cell death induction, characterized by cell cycle arrest in G 2 /M. The physiological validity of these observations was corroborated by the demonstration of intracellular FasL and APO2L/TRAIL expression in CD4 + and CD8 + T cell blasts, which were secreted in their bioactive form into the supernatant upon PHA, CD3 or CD59 reactivation. Additionally, the inhibition of IL-2-dependent CD4 + or CD8 + T cell blast growth upon CD3 or CD59 ligation was dependent, at least partially, on FasL and/or APO2L/TRAIL. These data precisely define the role of APO2L/TRAIL in the regulation of human T cell activation. IntroductionT cell tolerance, involving both central and peripheral mechanisms, is a complex process necessary to maintain normal homeostasis and to avoid autoimmunity. Several mechanisms account for the achievement of T cell peripheral tolerance, and defects in just one of them are normally associated with autoimmunity. Among these mechanisms are: (i) the induction of anergy through antigen presentation by non-APC, in the absence of co-stimulation, or by immature APC [1]; (ii) the action of regulatory T cells of CD4 + CD25 + phenotype [2]; and (iii) the termination of T cell immune responses [3].The regulated termination of T cell immune responses is dependent, in turn, on several complex and possibly overlapping cellular and molecular mechanisms. Of these could be cited the increased expression of the negative regulator CTLA-4 [4], IL-2 deprivation as a consequence of antigen exhaustion [5], and activationinduced cell death (AICD) of over-activated T cells [6]. This last mechanism was first reported to be dependent on the Fas/FasL system [7,8]. In fact, lpr and gld mice deficient in functional Fas or FasL expression, respectively [9,10], or humans with similar defects [11] have systemic autoimmune disease characterized by lymphoproliferation. Our group suggested for the first time the participation of APO2 ligand/TNF-related apoptosisinducing ligand (APO2L/TRAIL) and its receptors DR4 and DR5 in the down-regulation of T cell responses [12]. This participation has been confirmed recently in the APO2L/TRAIL knockout mice, which are more susceptible to autoimmune disease induction [13]. We have also found previously that FasL and APO2L/TRAIL are stored inside normal human T cell blasts in cytoplasmic compartments with characteristics of multivesicular bodies [14] and that they are rapidly released into the supernatant in their bioactive form associated with the internal microvesicles upon reactivation [14,15]. H...

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confidence: 60%

Human CD8+ T cell blasts are more sensitive than CD4+ T cell blasts to regulation by APO2L/TRAIL

et al. 2005

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“…72,73 Various harmful signals by ROS have been reported in aged cells. [31][32][33]42 We believe that the Prdx6 À/À LECs used in this study may represent a model that can be used to elucidate the signaling pathways involved in aged cells. Furthermore, our results show that reduction in transcription and attenuation of the DNA-binding activity of LEDGF are largely associated with ROS activation of TGFb in Prdx6 À/À LECs.…”

Section: Discussionmentioning

confidence: 95%

“…Our findings are in agreement with several reports demonstrating the activation of TGFb as a result of ROS elevation. 31,32,41,42 The most striking morphological differences between Prdx6 þ / þ cells and Prdx6 À/À cells are accounted for by expression pattern changes due to a single gene, Prdx6. The physiological consequences of Prdx6 knockout are notable.…”

Section: Introductionmentioning

confidence: 99%

Impaired homeostasis and phenotypic abnormalities in Prdx6−/−mice lens epithelial cells by reactive oxygen species: increased expression and activation of TGFβ

et al. 2005

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PRDX6, a member of the peroxiredoxins (PRDXs) family, is a key player in the removal of reactive oxygen species (ROS). Using targeted inactivation of the Prdx6 gene, we present evidence that the corresponding protein offsets the deleterious effects of ROS on lens epithelial cells (LECs) and regulates gene expression by limiting its levels. PRDX6-depleted LECs displayed phenotypic alterations and elevated a-smooth muscle actin and big-h3 expression (markers for cataractogenesis), indistinguishable from transforming growth factor b (TGFb)-induced changes. Biochemical assays disclosed enhanced levels of ROS, as well as high expression and activation of TGFb1 in Prdx6 À/À LECs. A CAT assay revealed transcriptional repression of lens epithelium-derived growth factor (LEDGF), HSP27, and aB-crystallin promoter activities in these cells. A gel mobility shift assay demonstrated the attenuation of LEDGF binding to heat shock or stress response elements present in these genes. A supply of PRDX6 toPrdx6 À/À LECs reversed these changes. Based on the above data, we propose a rheostat role for PRDX6 in regulating gene expression by controlling the ROS level to maintain cellular homeostasis.

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“…If Hg is interfering with CD95 signaling, then normal cell loss in response to SEB with or without Hg is not surprising given reports that the activation induced cell death (AICD) phase in response to SEB is CD95 independent (Hildeman et al, 1999;Hildeman et al, 2002). Rather, the termination phase in response to SEB has been shown to be dependent on reactive oxygen species and the proapoptotic protein BIM (Hildeman et al, 1999;Hildeman et al, 2002). Nevertheless, the number of Vβ8+ T-cells is slightly reduced during the peak expansion phase of the SEB response in Hg intoxicated mice compared with non-exposed mice.…”

Section: Mercury Intoxication Attenuates the Amplitude Of The Primarymentioning

confidence: 99%

Exposure to inorganic mercury in vivo attenuates extrinsic apoptotic signaling in Staphylococcal aureus enterotoxin B stimulated T-cells

Laiosa

Eckles

Langdon

et al. 2007

Toxicology and Applied Pharmacology

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The heavy metal mercury (Hg) is known to have immunomodulatory properties affecting lymphocyte signal transduction, death receptor signaling and autoimmunity. In this study we tested the hypothesis that Hg exposure would attenuate T-cell activation and caspase 8 and 3 activity in response to antigenic stimuli. To test this hypothesis, BALB/cJ mice were exposed to 10 mg/L mercuric chloride (HgCl 2 ) in their drinking water for two weeks followed injection with 20μg of the Staphylococcal aureus enterotoxin B (SEB) superantigen. Eighteen hours after SEB challenge, there was a statistically significant reduction in caspase 8 and caspase 3 enzyme activity in the SEB reactive Vβ8+ T-cells. The attenuated caspase activity in Hg exposed mice persisted for 48 hours after exposure. Moreover, activation of caspase 8 and caspase 3 was reduced by more than 60% in CD95 deficient MRL/MpJ-Fas lpr mice demonstrating caspase 8 and 3 activation in response to SEB is CD95 dependent. In addition to the effects of Hg on caspase activity, expression of the T-cell activation marker CD69 was also attenuated in SEB reactive Vβ8 T-cells in Hg-exposed mice. Moreover, CD69 expression in MRL/MpJ-Fas lpr mice was also reduced. Taken together the caspase and CD69 data support a role for CD95 in promoting a proapoptotic and activated state in SEB responsive T-lymphocytes and this state is attenuated by the autoimmune potentiating environmental agent mercury.

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Reactive Oxygen Species Regulate Activation-Induced T Cell Apoptosis

Cited by 452 publications

References 53 publications

Human CD8+ T cell blasts are more sensitive than CD4+ T cell blasts to regulation by APO2L/TRAIL

Human CD8+ T cell blasts are more sensitive than CD4+ T cell blasts to regulation by APO2L/TRAIL

Impaired homeostasis and phenotypic abnormalities in Prdx6−/−mice lens epithelial cells by reactive oxygen species: increased expression and activation of TGFβ

Exposure to inorganic mercury in vivo attenuates extrinsic apoptotic signaling in Staphylococcal aureus enterotoxin B stimulated T-cells

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