T cell recognition of self-antigen presenting cells by protein transfer assay reveals a high frequency of anti-myelin T cells in multiple sclerosis.

Although peripheral blood myelin-autoreactive T cells are thought to play a key role in multiple sclerosis, they are generally considered to have qualitative differences rather than quantitative ones when compared to those found in healthy individuals. Here, we revisited the assessment of myelin-autoreactive T cells in a new approach based on their combined ability to acquire membrane proteins from autologous antigen presenting cells, and to respond to whole myelin extract as the stimulating autoantigen. Using this approach, the myelin-autoreactive T cell frequency in patients with multiple sclerosis was found to be unexpectedly high (n = 22, subtracted values median 2.08%, range 0-6%; background median 1%, range 0-4%) and to exceed that of age/gender-matched healthy individuals significantly (n = 18, subtracted values median 0.1%, range 0-5.3%, P < 0.0001; background median 1.45%, range 0.1-4%). Higher anti-myelin autoreactivity was stable in patients with multiple sclerosis after several months. These data correlated with whole myelin-induced gamma interferon-enzyme-linked immunosorbent spot assay performed under the same conditions, although the values obtained with enzyme-linked immunosorbent spot assay under all conditions were 58 times lower than with this new method. The myelin-autoreactive T cells were memory T cells expressing CD40L with a CD62(low) phenotype, suggesting their ability for homing to tissues. Collectively, these new data show a higher frequency of autoreactive T cells during multiple sclerosis than in age/gender-matched healthy individuals, and support an autoimmune aetiology in multiple sclerosis.

[1]  P. Couraud,et al.  Peripheral blood CD4+ T lymphocytes from multiple sclerosis patients are characterized by higher PSGL‐1 expression and transmigration capacity across a human blood‐brain barrier‐derived endothelial cell line , 2009, Journal of leukocyte biology.

[2]  E. Joly,et al.  Improving administration regimens of CyaA-based vaccines using TRAP assays to detect antigen-specific CD8(+) T cells directly ex vivo. , 2009, Vaccine.

[3]  D. Laplaud,et al.  Patients with relapsing-remitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor alpha-chain are excluded from the analysis. , 2008, The Journal of clinical investigation.

[4]  S. Hillion,et al.  Blood CD8+ T cell responses against myelin determinants in multiple sclerosis and healthy individuals , 2008, European journal of immunology.

[5]  N. Hellings,et al.  Activation of myelin reactive T cells in multiple sclerosis: A possible role for T cell degeneracy? , 2008, European journal of immunology.

[6]  Raphael Gorodetsky,et al.  Capture of tumor cell membranes by trogocytosis facilitates detection and isolation of tumor-specific functional CTLs. , 2008, Cancer research.

[7]  P. Reichardt,et al.  The molecular makeup and function of regulatory and effector synapses , 2007, Immunological reviews.

[8]  J. Lünemann,et al.  Epstein-Barr virus and multiple sclerosis , 2007, Current neurology and neuroscience reports.

[9]  E. Carosella,et al.  Exchanges of membrane patches (trogocytosis) split theoretical and actual functions of immune cells. , 2007, Human immunology.

[10]  Hans Lassmann,et al.  The Immunopathology of Multiple Sclerosis: An Overview , 2007, Brain pathology.

[11]  E. Joly,et al.  Capture of Target Cell Membrane Components via Trogocytosis Is Triggered by a Selected Set of Surface Molecules on T or B Cells1 , 2007, The Journal of Immunology.

[12]  C. Beadling,et al.  Quantifying viable virus-specific T cells without a priori knowledge of fine epitope specificity , 2006, Nature Medicine.

[13]  C. Melief,et al.  Ins and Outs of Dendritic Cells , 2006, International Archives of Allergy and Immunology.

[14]  E. Joly,et al.  A very rapid and simple assay based on trogocytosis to detect and measure specific T and B cell reactivity by flow cytometry , 2006, European journal of immunology.

[15]  R. Hintzen,et al.  Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis. , 2006, Brain : a journal of neurology.

[16]  S. Reingold,et al.  Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria” , 2005, Annals of neurology.

[17]  Andreas Thiel,et al.  Direct access to CD4+ T cells specific for defined antigens according to CD154 expression , 2005, Nature Medicine.

[18]  L. Picker,et al.  Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects , 2005, The Journal of experimental medicine.

[19]  S. Miller,et al.  Immunotherapy Targeting the CD40/CD154 Costimulatory Pathway for Treatment of Autoimmune Disease , 2004, Autoimmunity.

[20]  V. Rivera,et al.  Increased CD8+ Cytotoxic T Cell Responses to Myelin Basic Protein in Multiple Sclerosis1 , 2004, The Journal of Immunology.

[21]  Clare Baecher-Allan,et al.  Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients with Multiple Sclerosis , 2004, The Journal of experimental medicine.

[22]  R. Simon,et al.  Expansion and Functional Relevance of High-Avidity Myelin-Specific CD4+ T Cells in Multiple Sclerosis , 2004, The Journal of Immunology.

[23]  N. Hellings,et al.  Functional properties of myelin oligodendrocyte glycoprotein-reactive T cells in multiple sclerosis patients and controls , 2003, Journal of Neuroimmunology.

[24]  D. Maric,et al.  Detection of virus-specific T cells and CD8+ T-cell epitopes by acquisition of peptide–HLA-GFP complexes: analysis of T-cell phenotype and function in chronic viral infections , 2003, Nature Medicine.

[25]  S. John,et al.  IL-2 Receptor Blockade Inhibits Late, But Not Early, IFN-γ and CD40 Ligand Expression in Human T Cells: Disruption of Both IL-12-Dependent and -Independent Pathways of IFN-γ Production , 2002, The Journal of Immunology.

[26]  S. Baig,et al.  Multiple MAG peptides are recognized by circulating T and B lymphocytes in polyneuropathy and multiple sclerosis , 2002, European journal of neurology.

[27]  L. Bruckers,et al.  Longitudinal study of antimyelin T-cell reactivity in relapsing–remitting multiple sclerosis: association with clinical and MRI activity , 2002, Journal of Neuroimmunology.

[28]  Roland Martin,et al.  Dendritic cells signal T cells in the absence of exogenous antigen , 2001, Nature Immunology.

[29]  Boris Barbour,et al.  Functional antigen-independent synapses formed between T cells and dendritic cells , 2001, Nature Immunology.

[30]  C. Poser,et al.  Diagnostic criteria for multiple sclerosis , 2001, Clinical Neurology and Neurosurgery.

[31]  Jingwu Z. Zhang,et al.  Reactivity pattern and cytokine profile of T cells primed by myelin peptides in multiple sclerosis and healthy individuals , 2001, European journal of immunology.

[32]  M. D'hooghe,et al.  T‐cell reactivity to multiple myelin antigens in multiple sclerosis patients and healthy controls , 2001, Journal of neuroscience research.

[33]  J. Bell,et al.  Functional Heterogeneity and High Frequencies of Cytomegalovirus-Specific CD8+ T Lymphocytes in Healthy Seropositive Donors , 2000, Journal of Virology.

[34]  Richard A. Rudick,et al.  Quantification of Self-Recognition in Multiple Sclerosis by Single-Cell Analysis of Cytokine Production1 , 2000, The Journal of Immunology.

[35]  C. Tournay,et al.  Efficient detection and immunomagnetic sorting of specific T cells using multimers of MHC class I and peptide with reduced CD8 binding , 2000, Nature Medicine.

[36]  D. Harlan,et al.  Cd40 Ligand (Cd154) Triggers a Short-Term Cd4+ T Cell Activation Response That Results in Secretion of Immunomodulatory Cytokines and Apoptosis , 2000, The Journal of experimental medicine.

[37]  Stephen L Hauser,et al.  Autoreactivity to myelin antigens: myelin/oligodendrocyte glycoprotein is a prevalent autoantigen , 1999, Journal of Neuroimmunology.

[38]  L. Amaducci,et al.  T-cell response to myelin basic protein and lipid-bound myelin basic protein in patients with multiple sclerosis and healthy donors , 1998, Journal of Neuroimmunology.

[39]  A. Ben-nun,et al.  Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: Reactivity to the extracellular domain of MOG is directed against three main regions , 1997, European journal of immunology.

[40]  D. Hafler,et al.  Direct Ex Vivo Analysis of Activated, Fas-sensitive Autoreactive T Cells in Human Autoimmune Disease , 1997, The Journal of experimental medicine.

[41]  H. Knigge,et al.  The outer surface lipoprotein OspA of Borrelia burgdorferi provides co‐stimulatory signals to normal human peripheral CD4+ and CD8+ T lymphocytes , 1996, European journal of immunology.

[42]  M. Croft,et al.  Regulation of CD40 ligand expression on naive CD4 T cells: a role for TCR but not co-stimulatory signals. , 1996, International immunology.

[43]  U. Schaible,et al.  The outer surface lipoprotein A of Borrelia burgdorferi provides direct and indirect augmenting/co-stimulatory signals for the activation of CD4+ and CD8+ T cells. , 1995, Immunology letters.

[44]  H. Weiner,et al.  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 , 1994, The Journal of experimental medicine.

[45]  D. Bourdette,et al.  Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis , 1992, Journal of Neuroimmunology.

[46]  T. Olsson,et al.  T and B cell responses to myelin-oligodendrocyte glycoprotein in multiple sclerosis. , 1991, Journal of immunology.

[47]  T. Olsson,et al.  Autoreactive T lymphocytes in multiple sclerosis determined by antigen-induced secretion of interferon-gamma. , 1990, The Journal of clinical investigation.

[48]  E. Joly,et al.  A simple trogocytosis-based method to detect, quantify, characterize and purify antigen-specific live lymphocytes by flow cytometry, via their capture of membrane fragments from antigen-presenting cells , 2006, Nature Protocols.

[49]  S. John,et al.  IL-2 receptor blockade inhibits late, but not early, IFN-gamma and CD40 ligand expression in human T cells: disruption of both IL-12-dependent and -independent pathways of IFN-gamma production. , 2002, Journal of immunology.