Signal transduction by HLA-DR is mediated by tyrosine kinase(s) and regulated by CD45 in activated T cells.
Recently, it was shown that HLA class II molecules on B cells and activated human T cells can transmit signals involving tyrosine phosphorylation of specific proteins, activation of the inositol phospholipid pathway, and release of cytosolic free Ca2+(Ca2+)i. The regulation of class II induced signals is poorly understood, however, and it remained unknown whether these pathways were coupled or activated independently. Here we show that a specific inhibitor of protein tyrosine kinases (PTK), herbimycin, abrogated DR-induced elevation of (Ca2+)i in activated human T cells. Genistein, belonging to another family of PTK inhibitors, had weaker but significant inhibitory effects on DR-induced (Ca2+)i responses. CD45 crosslinking with DR almost completely abrogated DR-induced (Ca2+)i responses and profoundly changed the PTK profiles. In contrast, CD4 crosslinking with DR enhanced the (Ca2+)i responses, but the inhibitory effect of CD45 dominated over the enhancing effect of CD4. These data indicate that PTK activation is obligatory for DR-induced (Ca2+)i responses, suggesting a linkage between these pathways in class II signal transduction. This conclusion is consistent with our observation that in activated human T cells, class II signals are up regulated by CD4, which is associated with p56lck, and down regulated by CD45, which is a tyrosine phosphatase.
Odum
N
N
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Martin
P J
PJ
Schieven
G L
GL
Norris
N A
NA
Grosmaire
L S
LS
Hansen
J A
JA
Ledbetter
J A
JA
D015703:Antigens, CD / Q000378:metabolism*; D016227:Benzoquinones; D015704:CD4 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002999:Clone Cells; D004789:Enzyme Activation; D006684:HLA-DR Antigens / Q000378:metabolism*; D006649:Histocompatibility Antigens / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic; D017493:Leukocyte Common Antigens; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D015703:Antigens, CD; D016227:Benzoquinones; D015704:CD4 Antigens; D006684:HLA-DR Antigens; D006649:Histocompatibility Antigens; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D017493:Leukocyte Common Antigens; D002118:Calcium