Immunoregulation of encephalitogenic MBP-NAc1-11-reactive T cells by CD4+ TCR-specific T cells involves IL-4, IL-10 and IFN-gamma.
The generation of TCR transgenic (Tg) mice expressing a BV8S2 (Vbeta8 subfamily 2) chain specific for the encephalitogenic NAc1-11 region of MBP provides a unique system for evaluating the mechanisms involved in anti-TCR immunoregulation of EAE. In a previous study, we showed that vaccination with BV8S2 protein induced specific T cells that inhibited proliferation responses and encephalitogenic activity of MBP-reactive T cells in vitro, and resulted in a skewed production of Th2 cytokines by the MBP-reactive T cells. These data suggested that regulation of the encephalitogenic T cells was mediated by inhibitory cytokines rather than through a deletional mechanism. In the current study, we have employed the BV8S2 Tg mouse model to address the issue of which cytokines produced by anti-TCR-reactive T cells can regulate the function of encephalitogenic Th1 cells. Utilizing neutralizing anti-cytokine antibodies to reverse inhibitory effects of supernatants from BV8S2-specific T cells, we found that IL-4, IL-10, and to a lesser extent, IFN-gamma and TGF-beta, were the major regulatory cytokines responsible for inhibiting encephalitogenic activity, proliferation, and IFN-gamma secretion of MBP-NAc1-11-reactive Th1 cells. These results indicate that cytokine regulation is the major mechanism through which TCR specific CD4+ T cells regulate encephalitogenic and potentially other bystander Th1 cells.
Adlard
K
K
Neuroimmunology Research, R&D-31, Veterans Affairs Medical Center, Portland, OR 97201, USA.
Tsaknardis
L
L
Beam
A
A
Bebo
B F
BF
Vandenbark
A A
AA
Offner
H
H
D029845:Amphibian Proteins; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002460:Cell Line; D018920:Coculture Techniques; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D006133:Growth Substances / Q000096:biosynthesis*; D007155:Immunologic Factors / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000276:immunology*; D009479:Neuropeptides; D010446:Peptide Fragments / Q000276:immunology*; D011506:Proteins / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D029845:Amphibian Proteins; C121344:Bv8 protein, Bombina variegata; D006133:Growth Substances; D007155:Immunologic Factors; D004676:Myelin Basic Protein; D009479:Neuropeptides; D010446:Peptide Fragments; D011506:Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C075784:T cell receptor Vbeta8; D016212:Transforming Growth Factor beta; C405722:myelin basic protein 1-11; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma