Distinctive signaling pathways through CD82 and beta1 integrins in human T cells.
CD82, a member of tetraspan family (tetraspanin), is a multifunctional molecule that is involved in cell activation, costimulation, and cell spreading of T cells. Here we show that immobilized anti-CD82 monoclonal antibody (mAb) as well as anti-alpha4beta1 integrin mAb induced tyrosine phosphorylation of pp105/Crk-associated substrate lymphocyte type (Cas-L) in human peripheral T cells and H9 cells. Furthermore, one of anti-CD82 mAb (8E4), which induces homotypic aggregation of T cells and H9 cells but has no costimulatory activity, partially inhibited very late antigen (VLA)-4 integrin ligand-mediated costimulation of T cells, whereas it failed to inhibit VLA-5 integrin ligand-mediated costimulation. To further elucidate the relationship between CD82- and VLA-4-mediated signaling pathways we defined the IL-2 production by the costimulation of Jurkat T cells with marginal amount of Cas-L, and subsequently found that mAb against CD82 had strong costimulatory activity to CD3/TCR, whereas mAb against beta1 failed to do so in those cells. We have further demonstrated that this discrepancy between beta1 integrin- and CD82-mediated costimulation partly lies in differential activation of NF-AT, AP-1, and NF-kappaB in Jurkat T cells. In this study, although some functional overlap exists, we provide evidence for distinctive signaling of CD82- and beta1 integrin-mediated costimulation at the transcriptional level of IL-2 gene.
Iwata
Satoshi
S
Division of Clinical Immunology, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Kobayashi
Hiroshi
H
Miyake-Nishijima
Rikako
R
Sasaki
Takahiro
T
Souta-Kuribara
Akiko
A
Nori
Mamoru
M
Hosono
Osamu
O
Kawasaki
Hiroshi
H
Tanaka
Hirotoshi
H
Morimoto
Chikao
C
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D039041:Integrin alpha4beta1; D019012:Integrin beta1 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics; D019169:Jurkat Cells; D051861:Kangai-1 Protein; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D017469:Receptors, Fibronectin / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C497688:CD82 protein, human; D004268:DNA-Binding Proteins; D039041:Integrin alpha4beta1; D019012:Integrin beta1; D016023:Integrins; D007376:Interleukin-2; D051861:Kangai-1 Protein; D008562:Membrane Glycoproteins; C099942:NEDD9 protein, human; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D017469:Receptors, Fibronectin; D016201:Receptors, Lymphocyte Homing; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014443:Tyrosine