Two mechanisms of antigen-specific apoptosis of myelin basic protein (MBP)-specific T lymphocytes derived from multiple sclerosis patients and normal individuals.

Several stimuli induce mature T cells to undergo apoptosis or programmed cell death (PCD) including specific Ag. We have demonstrated previously that Ag induces the death of encephalitogenic T cells in vitro and deletion in vivo, leading to amelioration of autoimmune encephalomyelitis. We have now examined whether activated, myelin basic protein (MBP)-specific human T cells may be eliminated by Ag-induced PCD. We demonstrate that activated MBP-specific T cell lines (TCL) undergo the classic nuclear morphologic changes and DNA fragmentation characteristic of apoptosis when given a TCR challenge. We found evidence that two mechanisms led to apoptosis: a propriocidal mechanism that was highly Ag-specific and dependent on the dose of exogenously added rIL-2, and a cytolytic mechanism in which MBP-specific TCL lysed B cell targets and engaged in considerable "fratricidal" cytolysis of other MBP-specific T cells. These two pathways leading to MBP-specific apoptotic death could be distinguished by their glucocorticoid sensitivity. Glucocorticoid treatment significantly blocked MBP-induced propriocidal apoptosis but had no effect on T cell cytolysis of B cell targets. Although it has been proposed that autoimmune disease could result from the failure of normal deletional mechanisms, this preliminary survey of MBP-reactive mature TCL from multiple sclerosis patients revealed that such cells are highly susceptible to TCR-induced PCD and comparable with TCL from normal subjects. Thus, therapeutic strategies based on Ag-induced PCD of T lymphocytes may be feasible in man.

• Publication year

  1995

• Venue

  Journal of Immunology

• Publication date

  1995-06-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.4049/jimmunol.154.11.6191PMID 7538545
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Susceptibility to cytotoxic T lymphocyte-induced apoptosis is a function of the proliferative status of the target

  1994cited by this paper
• Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand.

  1994cited by this paper
• Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis

  1994cited by this paper
• T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis.

  1994cited by this paper
• Identification of a second T cell epitore of human proteolipid protein (residues 89–106) recognized by proliferative and cytolytic CD4+ T cells from multiple sclerosis patients

  1994cited by this paper
• Fas antigen is the major target molecule for CD4+ T cell-mediated cytotoxicity.

  1994cited by this paper
• Participation of target Fas protein in apoptosis pathway induced by CD4+ Th1 and CD8+ cytotoxic T cells.

  1994cited by this paper
• Apoptotic cell death induced by intracellular proteolysis.

  1994cited by this paper
• Propriocidal apoptosis of mature T lymphocytes occurs at S phase of the cell cycle

  1993cited by this paper
• Glucocorticoids and irradiation-induced apoptosis in normal murine bone marrow B-lineage lymphocytes as determined by flow cytometry.

  1993cited by this paper
• Ligand-induced apoptosis of mature T lymphocytes (propriocidal regulation) occurs at distinct stages of the cell cycle.

  1993cited by this paper
• Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family.

  1993cited by this paper
• Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis.

  1993cited by this paper
• T helper 1 (Th1) functional phenotype of human myelin basic protein-specific T lymphocytes.

  1993cited by this paper
• Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity

  1993cited by this paper
• Identification of a novel T cell epitope of human proteolipid protein (residues 40-60) recognized by proliferative and cytolytic CD4+ T cells from multiple sclerosis patients.

  1993cited by this paper
• Cognate peptide-induced destruction of CD8+ cytotoxic T lymphocytes is due to fratricide.

  1993cited by this paper
• Signaling for death of lymphoid cells.

  1993cited by this paper
• Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas.

  1992cited by this paper
• The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen.

  1992cited by this paper
• Apoptosis and programmed cell death in immunity.

  1992cited by this paper
• Immunological aspects of demyelinating diseases.

  1992cited by this paper
• Dexamethasone inhibits human interleukin 2 but not interleukin 2 receptor gene expression in vitro at the level of nuclear transcription.

  1991cited by this paper
• T cell-T cell killing is induced by specific epitopes: evidence for an apoptotic mechanism

  1991cited by this paper
• A myelin basic protein peptide is recognized by cytotoxic T cells in the context of four HLA-DR types associated with multiple sclerosis

  1991cited by this paper
• Pharmacodynamics of Methylprednisolone Phosphate After Single Intravenous Administration to Healthy Volunteers

  1991cited by this paper
• The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis.

  1991cited by this paper
• Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis.

  1991cited by this paper
• The JAM test. A simple assay for DNA fragmentation and cell death.

  1991cited by this paper
• In vivo administration of monoclonal antibodies to the CD3 T cell receptor complex induces cell death (apoptosis) in immature thymocytes.

  1991cited by this paper
• HLA-DR2a is the dominant restriction molecule for the cytotoxic T cell response to myelin basic protein in DR2Dw2 individuals.

  1990cited by this paper
• Programmed T lymphocyte death. Cell activation- and steroid-induced pathways are mutually antagonistic.

  1990cited by this paper
• Transgenic Models of T‐Cell Self Tolerance and Autoimmunity

  1990cited by this paper
• Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals.

  1990cited by this paper
• Programmed death of autoreactive thymocytes

  1990cited by this paper
• Specific killing of cytotoxic T cells and antigen-presenting cells by CD4+ cytotoxic T cell clones. A novel potentially immunoregulatory T-T cell interaction in man

  1990cited by this paper
• Purified perforin induces target cell lysis but not DNA fragmentation

  1989cited by this paper
• Monoclonal antibody-mediated tumor regression by induction of apoptosis.

  1989cited by this paper
• Quantitative magnetic resonance imaging in multiple sclerosis: the effect of high dose intravenous methylprednisolone.

  1989cited by this paper
• Immunological studies of the pathogenesis of multiple sclerosis Cell‐mediated cytotoxicity by peripheral blood lymphocytes against basic protein of myelin, encephalitogenic peptide, cerebrosides and gangliosides

  1989cited by this paper
• Methylprednisolone and multiple sclerosis.

  1988cited by this paper
• Resistance of cytotoxic T lymphocytes to the lytic effects of their toxic granules

  1987cited by this paper
• Resistance of cloned cytotoxic T lymphocytes to cell-mediated cytotoxicity

  1987cited by this paper
• Resistance of cytotoxic T lymphocytes to lysis by a clone of cytotoxic T lymphocytes.

  1987cited by this paper
• Chromatin cleavage in apoptosis: Association with condensed chromatin morphology and dependence on macromolecular synthesis

  1984cited by this paper
• Multiple Sclerosis as a Disease of Immune Regulation

  1984cited by this paper
• Multiple sclerosis (first of two parts).

  1982cited by this paper
• Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation

  1980cited by this paper
• Has myelin basic protein received a fair trial in the treatment of multiple sclerosis?

  1979cited by this paper
• Failure of basic protein therapy for multiple sclerosis

  1977cited by this paper
• Myelin basic protein administration in multiple sclerosis.

  1973cited by this paper
• Large scale preparation of myelin basic protein from central nervous tissue of several mammalian species.

  1972cited by this paper

• Peptide of Myelin Basic Protein in Multiple Cells Recognizing an Immunodominant 13.1 T β A Common TCR V-D-J Sequence in V

  2013cites this paper
• Identification of astrocyte-derived immune suppressor factor that induces apoptosis of autoreactive T cells.

  2011cites this paper
• Mouse models for the study of autoimmune type 1 diabetes: a NOD to similarities and differences to human disease

  2010cites this paper
• Involvement of IFN-γ and perforin, but not Fas/FasL interactions in regulatory T cell-mediated suppression of experimental autoimmune encephalomyelitis.

  2010cites this paper
• Disease PD-L 1 in Patients with Different Patterns of Sclerosis : Distinctive Expression of PD-1 and Costimulatory Pathways in Multiple

  2009cites this paper
• Autoimmunity—Aging Mouse Model for Autoimmune Diseases

  2009cites this paper
• Didox modulates reactive oxygen species production and inflammatory events induced by lipopolysaccharide (LPS) and aryl hydrocarbon receptor (AHR) ligands in raw 264.7 murine macrophages

  2009cites this paper
• Costimulatory Pathways in Multiple Sclerosis: Distinctive Expression of PD-1 and PD-L1 in Patients with Different Patterns of Disease1

  2009cites this paper
• Cysteine protease activation and apoptosis in Murine norovirus infection

  2009cites this paper
• Investigating host response to viral infection through proteomics : a study of murine norovirus

  2008cites this paper
• Similar sensitivity of regulatory T cells towards CD95L-mediated apoptosis in patients with multiple sclerosis and healthy individuals.

  2006cites this paper
• Programmed cell death of myelin basic protein-specific T lymphocytes is reduced in patients with acute multiple sclerosis.

  2005cites this paper
• TCR signaling inhibits glucocorticoid‐induced apoptosis in murine thymocytes depending on the stage of development

  2005cites this paper
• Apoptosis and estrogen deficiency in primary Sjögren syndrome

  2004cites this paper
• Development of autoimmune arthritis with aging via bystander T cell activation in the mouse model of Sjögren's syndrome.

  2004cites this paper
• Crucial Role of Tissue-specific Apoptosis on the Development of Primary Sjögren's Syndrome

  2004cites this paper
• Corticosteroids treatment.

  2004cites this paper
• Time course of T-cell responses to MOG and MBP in patients with clinically isolated syndromes.

  2003cites this paper
• Direkter ex vivo Nachweis Myelin Bacis Protein (MBP)-spezifischer T-Helferzellen bei Multiple Sklerose Patienten

  2003cites this paper
• STEM CELL CHIMERISM AND TOLERANCE INDUCTION

  2001cites this paper
• Possible Role of Organ-Specific Autoantigen for Fas Ligand-Mediated Activation-Induced Cell Death in Murine Sjögren’s Syndrome1

  2001cites this paper
• Hematopoietic Stem Cell Chimerism and Tolerance Induction

  2001cites this paper
• Demyelinating Disease Regulatory T Cells During Autoimmune Modified Spreading Cascade with Genetically Pre-Emptive Targeting of the Epitope

  2001cites this paper
• Genes and cellular requirements for autoimmune diabetes susceptibility in nonobese diabetic mice.

  2001cites this paper
• T-cell vaccination in multiple sclerosis: immunoregulatory mechanism and prospects for therapy.

  2001cites this paper
• Pre-Emptive Targeting of the Epitope Spreading Cascade with Genetically Modified Regulatory T Cells During Autoimmune Demyelinating Disease1

  2001cites this paper
• Apoptosis in interface membranes of aseptically loose total hip arthroplasty

  2001cites this paper
• Cell Death in Murine Sjögren's Syndrome for Fas Ligand-Mediated Activation-Induced Possible Role of Organ-Specific Autoantigen

  2001cites this paper
• GLUCOCORTICOIDS IN TC ELL DEVELOPMENT AND FUNCTION

  2000cites this paper
• The effect of apoptosis inhibitors on experimental autoimmune encephalomyelitis: apoptosis as a regulatory factor.

  2000cites this paper
• Epitope spreading: a mechanism for progression of autoimmune disease.

  2000cites this paper
• Glucocorticoids in T cell development and function*.

  2000cites this paper
• Impaired Fas-independent apoptosis of T lymphocytes in patients with multiple sclerosis.

  2000cites this paper
• Differential Responses of Invariant Vα24JαQ T Cells and MHC Class II-Restricted CD4+ T Cells to Dexamethasone

  1999cites this paper
• Dual Role for Fas Ligand in the Initiation of and Recovery from Experimental Allergic Encephalomyelitis

  1999cites this paper
• Impaired apoptotic deletion of myelin basic protein‐reactive T cells in patients with multiple sclerosis

  1999cites this paper
• Spontaneous Regression of Primary Autoreactivity during Chronic Progression of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

  1999cites this paper
• A common TCR V-D-J sequence in V beta 13.1 T cells recognizing an immunodominant peptide of myelin basic protein in multiple sclerosis.

  1999cites this paper
• Nasal administration of transforming growth factor-β1 induces dendritic cells and inhibits protracted-relapsing experimental allergic encephalomyelitis

  1999cites this paper
• Regression and spreading of self-recognition during the development of autoimmune demyelinating disease.

  1999cites this paper
• Differential responses of invariant V alpha 24J alpha Q T cells and MHC class II-restricted CD4+ T cells to dexamethasone.

  1999cites this paper
• Mature T lymphocyte apoptosis--immune regulation in a dynamic and unpredictable antigenic environment.

  1999cites this paper
• T cell responses to myelin basic protein in patients with spinal cord injury and multiple sclerosis.

  1999cites this paper
• Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulin-dependent diabetes mellitus.

  1999cites this paper
• Astrocytes induce hyporesponses of myelin basic protein-reactive T and B cell function.

  1998cites this paper
• Antigen-Induced Death of T-Lymphocytes

  1998cites this paper
• Nitric oxide synthase inhibitor, aminoguanidine, reduces inflammation and demyelination produced by Theiler's virus infection.

  1998cites this paper
• Induction of apoptosis in a macrophage cell line RAW 264.7 by acemannan, a beta-(1,4)-acetylated mannan.

  1998influential citation
• Soluble Fas (Apo-1) levels in cerebrospinal fluid of multiple sclerosis patients

  1998cites this paper
• The role of apoptosis in neurodegenerative diseases.

  1997cites this paper
• Activation of T-cells through an antigen-independent alternative pathway induces precocious sensitivity to Fas-induced apoptosis.

  1997cites this paper
• Human autoreactive and foreign antigen-specific T cells resist apoptosis induced by soluble recombinant CD95 ligand.

  1997cites this paper
• Antigen-induced death of T-lymphocytes.

  1997cites this paper
• The generation of encephalitogenic T cell lines from experimental allergic encephalomyelitis-resistant strains of mice.

  1997cites this paper
• Fushi-ka (defective apoptosis) and rheumatic autoimmune diseases: an overview on the regulation of Fas-mediated T cell apoptotic signal transduction

  1997cites this paper
• Diversity and plasticity of self recognition during the development of multiple sclerosis.

  1997cites this paper
• Direct Ex Vivo Analysis of Activated, Fas-sensitive Autoreactive T Cells in Human Autoimmune Disease

  1997cites this paper
• Fas/APO‐1 (CD95)‐mediated cytotoxicity is responsible for the apoptotic cell death of leukaemic cells induced by interleukin‐2‐activated T cells

  1997cites this paper
• Nitric oxide via an inducible isoform of nitric oxide synthase is a possible factor to eliminate inflammatory cells from the central nervous system of mice with experimental allergic encephalomyelitis.

  1997cites this paper
• Characterization of lpr-derived T cell hybridomas: Fas-deficient hybridomas are deathless, growth-arrested, and cytotoxic upon activation.

  1996cites this paper
• MHC Class l‐Mediated Cytotoxicity Does Not Induce Apoptosis in Muscle Fibers nor in Inflammatory T Cells: Studies in Patients with Polymyositis, Dermatomyositis, and Inclusion Body Myositis

  1996cites this paper
• Intravenous antigen adrmnistration as a therapy for autoimmune demyelinating disease

  1996cites this paper
• Apoptosis--molecular mechanisms and biomedical implications.

  1996cites this paper
• Antigen-presenting cell engineering. The molecular toolbox.

  1996cites this paper
• Mechanisms of apoptosis as drug targets in the central nervous system

  1996cites this paper
• Increased Fas antigen on T cells in multiple sclerosis.

  1996cites this paper
• T cell response to two immunodominant proteolipid protein (PLP) peptides in multiple sclerosis patients and healthy controls

  1996cites this paper
• Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.

  1995influential citation