Human CD8+ TCR-alpha beta(+) and TCR-gamma delta(+) cells modulate autologous autoreactive neuroantigen-specific CD4+ T-cells by different mechanisms.
To investigate the regulatory interactions among autologous T-cells during the course of multiple sclerosis (MS), proteolipid protein peptide-specific CD4+ T-cell clones (TCCs) were irradiated and used as immunogens to stimulate purified populations of autologous CD8+ TCR-alpha beta+ and TCR-gamma delta+ T-cells isolated from the peripheral blood of MS patients, patients with other non-inflammatory neurological diseases, and healthy blood donors. The resulting blasts were expanded in the presence of hIL-2 and then cloned by limiting dilution. Two different groups of CD8+ TCCs were revealed. A first group of CD8+ TCCs recognized autologous CD4+ T-cells based in their TCRV beta structures (anti-idiotypic responsiveness). A second group of CD8+ TCCs recognized Ag activated autologous CD4+ TCCs irrespective of their Ag specificity or TCRV beta expression (anti-ergotypic responsiveness). Both groups showed MHC class I restricted cytotoxicity against CD4+ T-cells and were able to secrete IFN-gamma, TNF alpha/beta and TGF-beta. TCR-gamma delta+ TCCs isolated in response to stimulation with autologous peptide-specific CD4+ TCCs showed only anti-ergotypic cytotoxicity, which was not inhibited by anti-MHC class Ia monoclonal antibodies. Moreover, they were able to secrete IFN-gamma and TNF alpha/beta, but not TGF-beta. These data demonstrate that regulatory mechanisms among human autologous T-cells can be mediated by cytolytic interactions or by the release of specific cytokines. Furthermore, they provide evidence that CD8+ TCR-alpha beta+ and TCR-gamma delta+ cells differ in their patterns of recognition and in their abilities to modulate the immune response mediated by autologous autoreactive CD4+ T-cells.
Correale
J
J
Department of Neurology, USC School of Medicine, Los Angeles 90033, USA.
Rojany
M
M
Weiner
L P
LP
D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002469:Cell Separation; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008233:Lymphotoxin-alpha / Q000378:metabolism; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001324:Autoantigens; D016207:Cytokines; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D018836:Inflammation Mediators; D008233:Lymphotoxin-alpha; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma