Cytokine phenotype of human autoreactive T cell clones specific for the immunodominant myelin basic protein peptide (83-99).
Experimental allergic encephalomyelitis (EAE), an animal model resembling multiple sclerosis (MS), is mediated by myelin antigen-specific CD4+ T cells secreting cytokines such as interferon-gamma (IFN-gamma), tumor necrosis factor-beta (TNF-beta), and the proinflammatory cytokine TNF-alpha-all associated with the T-helper-1 (Th1) T cell subset. Based on numerous similarities between MS and EAE, it has been postulated that Th1-like T cells are involved in the pathogenesis of MS. Production of proinflammatory cytokines such as IFN-gamma and, in particular, TNF-alpha/beta by autoreactive T cells is considered crucial for the initiation and amplification of inflammatory brain lesions and possibly also for direct myelin damage. In contrast, regulatory cytokines such as interleukin-4 (IL-4), IL-10, and IL-13, which are associated with the Th2-like phenotype, may play a role in the resolution of relapses. Although the human T cell response to myelin basic protein (MBP) is well characterized in terms of antigen specificity, HLA restriction, and T cell-receptor (TCR) usage, little is known about the cytokine pattern of these autoreactive T cells. To gain such information, conditions for studying cytokine secretion by human autoreactive T cell clones (TCC) were established. The cytokine secretion profile of human autoreactive CD4+ TCC, specific for myelin basic protein peptide (83-89) [MBP(83-99)], a candidate autoantigen in MS, was investigated. Our results show that TCC cytokine production in long-term culture was stable. In addition, the correlation of various cytokines within specific TCC revealed differences compared to murine T cells. The comparison of 30 human MBP (83-99)-specific TCC demonstrated heterogeneity in cytokine secretion, with a continuum between Th1- and Th2-like cells rather than distinct Th1 or Th2 subsets. These data are important for further investigation of the potential role of cytokines in the inflammatory process of MS, and provide a powerful tool to investigate therapeutic interventions with respect to their influence on cytokine secretion of autoreactive T cells.
Hemmer
B
B
Neuroimmunology Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892-1400, USA.
Vergelli
M
M
Calabresi
P
P
Huang
T
T
McFarland
H F
HF
Martin
R
R
D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000097:blood*; D002999:Clone Cells; D016207:Cytokines / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte; D006801:Humans; D016056:Immunodominant Epitopes; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology / Q000503:physiopathology*; D004676:Myelin Basic Protein / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology*
D001323:Autoantibodies; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C104448:myelin basic protein 83-99