TY - JOUR

T1 - Signal transduction by HLA-DR is mediated by tyrosine kinase(s) and regulated by CD45 in activated T cells

AU - Odum, Niels

AU - Martin, P J

AU - Schieven, G L

AU - Norris, N A

AU - Grosmaire, L S

AU - Hansen, J A

AU - Ledbetter, J A

N1 - Keywords: Antigens, CD; Antigens, CD4; Antigens, CD45; Benzoquinones; Calcium; Cells, Cultured; Clone Cells; Enzyme Activation; HLA-DR Antigens; Histocompatibility Antigens; Humans; Lactams, Macrocyclic; Protein-Tyrosine Kinases; Quinones; Signal Transduction; T-Lymphocytes

PY - 1991

Y1 - 1991

N2 - 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.

AB - 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.

M3 - Journal article

C2 - 1835971

VL - 32

SP - 85

EP - 94

JO - Human Immunology

JF - Human Immunology

SN - 0198-8859

IS - 2

ER -