Cross-linking HLA-DR molecules on Th1 cells induces anergy in association with increased level of cyclin-dependent kinase inhibitor p27(Kip1).
HLA class II molecules play pivotal roles in antigen presentation to CD4+ T cells. We investigated signaling via HLA-DR molecules expressed on CD4+ T cells. 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. Whereas cross-linking of HLA-DR and CD3 resulted in secretion of the same levels of IFN-gamma and IL-8, secretion of IL-10 induced by cross-linking of HLA-DR was less than that induced by cross-linking of CD3 on CD4+ T cells. Interestingly, expression of p27(Kip1) but not p21(Cip1) increased after stimulation by either anti-HLA-DR or anti-CD3 mAb. This was indeed the case, when T cells were rendered anergic using a soluble form of antigenic peptide. In contrast, T cells stimulated by peptide-pulsed PBMC expressed little p27(Kip1). We propose that signaling via HLA-DR molecules on CD4+ T cells at least in part contributes to the induction of T cell anergy, through the upregulated expression of the p27(Kip1). The implication of our finding is that HLA-DR molecules play a role in human T cell anergy induced by a soluble form of antigenic peptide.
Kudo
Hironori
H
Department of Neuroscience and Immunology, Division of Immunogenetics, Kumamoto University Graduate School of Medical Sciences, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
Matsuoka
Takako
T
Mitsuya
Hiroaki
H
Nishimura
Yasuharu
Y
Matsushita
Sho
S
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000276:immunology*; D002455:Cell Division; D002460:Cell Line; D017635:Clonal Anergy / Q000276:immunology*; D003432:Cross-Linking Reagents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000096:biosynthesis; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D010455:Peptides; D012995:Solubility; D018417:Th1 Cells / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000276:immunology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D015704:CD4 Antigens; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D003432:Cross-Linking Reagents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006684:HLA-DR Antigens; D010455:Peptides; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases