Restimulation-Induced Cell Death (RICD): Methods for Modeling, Investigating, and Quantifying RICD Sensitivity in Primary Human T Cells via Flow Cytometric Analysis (original) (raw)
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The power and the promise of restimulation-induced cell death in human immune diseases
Immunological Reviews, 2010
Controlled expansion and contraction of lymphocytes both during and after an adaptive immune response is imperative to sustaining a healthy immune system. Both extrinsic and intrinsic pathways of lymphocyte apoptosis are programmed to eliminate cells at the proper time to ensure immune homeostasis. Genetic disorders of apoptosis described in mice and humans have established Fas and Bim as critical pro-apoptotic molecules responsible for T-cell death in response to T-cell receptor restimulation and cytokine withdrawal, respectively. Emerging evidence prompts revision of this classic paradigm, especially for our understanding of restimulation-induced cell death (RICD) and its physiological purpose. Recent work indicates that RICD employs both Fas and Bim for T-cell deletion, dispelling the notion that these molecules are assigned to mutually exclusive apoptotic pathways. Furthermore, new mouse model data combined with our discovery of defective RICD in X-linked lymphoproliferative disease (XLP) patient T cells suggest RICD is essential for precluding excess T-cell accumulation and associated immunopathology during the course of certain infections. Here we review how these advances offer a refreshing new perspective on the phenomenon of T-cell apoptosis induced through antigen restimulation, including its relevance to immune homeostasis and potential for therapeutic interventions.
Sensitivity to Restimulation-Induced Cell Death Is Linked to Glycolytic Metabolism in Human T Cells
The Journal of Immunology, 2016
Restimulation-induced cell death (RICD) regulates immune responses by restraining effector T cell expansion and limiting nonspecific damage to the host. RICD is triggered by re-engagement of the TCR on a cycling effector T cell, resulting in apoptosis. It remains unclear how RICD sensitivity is calibrated in T cells derived from different individuals or subsets. In this study we show that aerobic glycolysis strongly correlates with RICD sensitivity in human CD8+ effector T cells. Reducing glycolytic activity or glucose availability rendered effector T cells significantly less sensitive to RICD. We found that active glycolysis specifically facilitates the induction of proapoptotic Fas ligand upon TCR restimulation, accounting for enhanced RICD sensitivity in highly glycolytic T cells. Collectively, these data indicate that RICD susceptibility is linked to metabolic reprogramming, and that switching back to metabolic quiescence may help shield T cells from RICD as they transition into...
Regulation of activation-induced cell death of mature T-lymphocyte populations
Cell and Tissue Research, 2000
Resting mature T lymphocytes are activated when triggered via their antigen-specific T-cell receptor (TCR) to elicit an appropriate immune response. In contrast, preactivated T cells may undergo activation-induced cell death (AICD) in response to the same signals. Along with cell death induced by growth factor deprivation, AICD followed by the elimination of useless or potentially harmful cells preserves homeostasis, leads to the termination of cellular immune responses and ensures peripheral tolerance. T-cell apoptosis and AICD are controlled by survival cytokines such as interleukin-2 (IL-2) and by death factors such as tumor necrosis factor (TNF) and CD95 ligand (CD95L). In AICD-sensitive T cells, stimulation upregulates expression of one or several death factors, which in turn engage specific death receptors on the same or a neighboring cell. Death receptors are activated by oligomerization to rapidly assemble a number of adapter proteins and enzymes to result in an irreversible activation of proteases and nucleases that culminates in cell death by apoptosis. Increased knowledge of the molecular mechanisms that regulate AICD of lymphocytes opens new immunotherapeutic perspectives for the treatment of certain autoimmune diseases, and has implications in other areas such as transplantation medicine and AIDS research.
Critical role for BIM in T cell receptor restimulation-induced death
Biology Direct, 2008
Background Upon repeated or chronic antigen stimulation, activated T cells undergo a T cell receptor (TCR)-triggered propriocidal cell death important for governing the intensity of immune responses. This is thought to be chiefly mediated by an extrinsic signal through the Fas-FasL pathway. However, we observed that TCR restimulation still potently induced apoptosis when this interaction was blocked, or genetically impaired in T cells derived from autoimmune lymphoproliferative syndrome (ALPS) patients, prompting us to examine Fas-independent, intrinsic signals. Results Upon TCR restimulation, we specifically noted a marked increase in the expression of BIM, a pro-apoptotic Bcl-2 family protein known to mediate lymphocyte apoptosis induced by cytokine withdrawal. In fact, T cells from an ALPS type IV patient in which BIM expression is suppressed were more resistant to restimulation-induced death. Strikingly, knockdown of BIM expression rescued normal T cells from TCR-induced death t...
Cell Death & Disease, 2021
Immune homeostasis depends upon effective clearance of pathogens while simultaneously preventing autoimmunity and immunopathology in the host. Restimulation-induced cell death (RICD) is one such mechanism where by activated T cells receive subsequent antigenic stimulation, reach a critical signal threshold through the T cell receptor (TCR), and commit to apoptosis. Many details of this process remain unclear, including the role of co-stimulatory and co-inhibitory proteins that influence the TCR signaling cascade. Here we characterize the role of T cell immunoglobulin and mucin domain containing 3 (TIM-3) in RICD regulation. TIM-3 protected newly activated CD8+ effector T cells from premature RICD during clonal expansion. Surprisingly, however, we found that TIM-3 potentiated RICD in late-stage effector T cells. The presence of TIM-3 increased proximal TCR signaling and proapoptotic protein expression in late-stage effector T cells, with no consistent signaling effects noted in newly...
Differential ability of T cell subsets to undergo activation-induced cell death
Proceedings of the National Academy of Sciences, 1997
Human T cell clones were analyzed for their susceptibility to activation-induced cell death (AICD) in response to CD3͞T cell receptor ligation. AICD was observed only in Th1 clones and was Fas-mediated, whereas Th2 clones resisted AICD. Analysis of a panel of Th0 clones, characterized by their ability to secrete both Th1 and Th2 cytokines, revealed that this subset included both AICD-sensitive (type A) and -resistant (type B) clones. Resistance to AICD by Th2 and Th0-type B clones was not due to lack of expression of either Fas receptor or its ligand. Paradoxically, the AICDresistant clones were susceptible to apoptosis when Fas receptor was directly ligated by anti-Fas antibodies. However, prior activation of the resistant clones by monoclonal antibodies to CD3͞TCR complex induced resistance against Fasmediated apoptosis. Thus, the Fas-FasL pathway is critical for the induction of AICD in T cells, and moreover this pathway can be negatively regulated in the AICD-resistant clones by signals that are generated from ligation of the CD3͞TCR complex.
Experimental Gerontology, 1996
The growth characteristics in vitro of interleukin 2 (IL 2)-dependent human CD4 ÷ c¢13-T cell receptor-positive helper T cell clones (TCC) were studied in relation to alterations in surface phenotype, cytokine responsiveness, and susceptibility to activationinduced cell death (AICD). TCC derived from peripheral blood T cells had finite lifespans averaging 33 population doublings (PD) with a recorded maximum lifespan of 80 PD (n = 208). First analyses of the TCC were undertaken at ca. 25 PD, at which time all cells of all TCC expressed high intensity CD45RO and low intensity CD45RA, as well as high intensity CD95 (fas) and MHC class II antigens. The expression of these molecules remained elevated throughout the proliferative lifespan of the clones, but for those TCC which were initially CD28 ÷ (the majority), the density of expression of the latter was diminished in most latepassage clones. Concomitant with this, late-passage cells showed reduced responsiveness to CD28-mediated costimulation by CHO transfectants expressing human CDS0 compared to early-passage cells. Additionally, the level of expression of IL 2R',/c and IL 7R chains was commonly reduced, as was the response to IL 2 and IL 7. Despite unchanged levels of fas expression on TCC with time, late-passage cells were more susceptible to AICD than earlypassage cells. These observations further document functional and phenotypic alterations in long-term cultured human T helper cells, which may be considered as biomarkers of immunosenescence. This may contribute to an improved understanding of the mechanisms underlying depressed T cell function in old age. 655 656 G PAWELEC et al.