title: Activated self-MHC-reactive T cells have the cytokine phenotype of Th3/T regulatory cell 1 T cells.
abstract: In the present study, we show that human self-MHC-reactive (autoreactive) T cell clones are functionally distinct from Ag-specific T cell clones. Self-MHC-reactive T cells exhibited helper function for B cell Ig production when cultured with non-T cells alone, and they exhibit suppressor function when cultured with PWM- or rCD40 ligand (rCD40L)-activated non-T cells, whereas tetanus toxoid (TT)-specific clones exhibited only helper function in the presence of TT with or without PWM or rCD40L. Addition of neutralizing Abs to the cultures showed that the suppression was mediated by TGF-beta but not by IL-10 or IFN-gamma. The self-MHC-reactive clones also inhibited proliferation of primary CD4+ T cells and TT-specific T cell clones, but in this case the inhibition was mediated by both IL-10 and TGF-beta. In further studies, the interactions between self-MHC-reactive T cell clones and non-T cells that led to suppressor cytokine production have been explored. We found that prestimulation of non-T cells for 8 h with PWM or for 48 h for rCD40L results in non-T cells capable of inducing self-MHC-reactive T cell to produce high levels of TGF-beta and IL-10. In addition, these prestimulation times coincided with peak induction of HLA-DR and costimulatory B7 molecule (especially CD86) expression on B cells. Finally, addition of CTLA-4/Fc or blocking F(ab')2 anti-CTLA-4 mAb, plus optimally stimulated non-T cells, to cultures of self-MHC-reactive clones inhibited the induction of TGF-beta but not IL-10 or IFN-gamma production. In summary, these studies show that activated self-MHC-reactive T cells have the cytokine phenotype of Th3 or T regulatory cell 1 and thus may be important regulatory cells that mediate oral and peripheral tolerance and prevent the development of autoimmunity.
authors.affiliation: Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kitani
authors.forename: K
authors.initials: K
authors.lastname: Chua
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: W
authors.initials: W
authors.lastname: Strober
mesh_terms: D000069594:Abatacept; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D002999:Clone Cells / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D018796:Immunoconjugates; D007136:Immunoglobulins / Q000096:biosynthesis; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000494:pharmacology; D011043:Pokeweed Mitogens / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000145:classification* / Q000276:immunology / Q000378:metabolism; D013745:Tetanus Toxoid / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; D018796:Immunoconjugates; D007136:Immunoglobulins; D008024:Ligands; D008562:Membrane Glycoproteins; D011043:Pokeweed Mitogens; D011994:Recombinant Proteins; D013745:Tetanus Toxoid; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D023201:CD40 Ligand; D000069594:Abatacept