When HLA-DR, -DQ and -DP molecules were cross-linked by solid-phase mAbs, monocytes produced monokines, and only anti-DR Ab markedly activates MAP kinase Erk, whereas anti-DR, anti-DQ and anti-DP all activate MAP kinase p38. DR-restricted T cells that are established from PBMC and are reactive with mite antigens, PPD and random 19-mer peptides, exhibited higher IFN-γ: IL-4 ratio than did DQ- or DP-restricted T cells. These results indicate that HLA-DR, -DQ and -DP molecules transmit distinct signals to monocytes via MAP kinases and lead to distinct monokine activation patterns, which may affect T-cell responses in vivo. Thus, the need for generation of a multigene family of class II MHC seems apparent. HLA-DR on B cells, on the other hand, not only present antigenic peptides to T cells, but also up-regulate IgM production, in association with Syk activation. When HLA-DR or CD3 molecules on cloned CD4+ T cells were cross-linked by solid-phase mAbs, T cells proliferated, and this resulted in anergy. We propose that signaling via HLA-DR molecules on CD4+ T cells at least in part contributes to the induction of T cell anergy that can be induced by soluble form of antigenic peptide. We next used IFN-γ-treated and irradiated periodontal ligament fibroblasts (PDL) expressing HLA-DR molecules. Indeed, Th cells did not show proliferative responses when peptide-pulsed PDL were used as APC, whereas PDL produced larger amounts of IL-6, IL-8, MCP-1 and RANTES compared with controls, when cultuted with anti-HLA-DR mAb or emetine-treated T cells. These findings suggest that HLA-DR expressed on fibroblasts may act as receptor molecules that transmit signals into fibroblasts, based on DR-peptide-TCR interaction, resulting in the secretion of several cytokine species.
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