Activated self-MHC-reactive T cells have the cytokine phenotype of Th3/T regulatory cell 1 T cells

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 wh en cultured with non-T cells alone, and they exhibit suppressor function wh en cultured with PWM- or rCD40 ligand (rCD40L)-activated non-T cells, where as tetanus toroid (TT)-specific clones exhibited only helper function in th e presence of TT with or without PWM or rCD40L, Addition of neutralizing Ab s 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 prol iferation of primary CD4(+) T cells and TT-specific T cell clones, but in t his 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 f ound that prestimulation of non-T cells for 8 h with PWM or for 48 h for rC D40L 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 prestimulati on times coincided with peak induction of HLA-DR and costimulatory B7 molec ule (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 cel ls, 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 med iate oral and peripheral tolerance and prevent the development of autoimmun ity.