TY - JOUR
T1 - ZAP-70 and p72syk are signaling response elements through MHC class II molecules
AU - Kanner, S B
AU - Grosmaire, L S
AU - Blake, J
AU - Schieven, G L
AU - Masewicz, S
AU - Odum, Niels
AU - Ledbetter, J A
N1 - Keywords: CD4-Positive T-Lymphocytes; Enzyme Activation; Enzyme Precursors; HLA-DR Antigens; Humans; Intracellular Signaling Peptides and Proteins; Lymphocyte Activation; Protein-Tyrosine Kinases; Receptors, Antigen, T-Cell; Signal Transduction; ZAP-70 Protein-Tyrosine Kinase
PY - 1995
Y1 - 1995
N2 - Ligation of major histocompatibility complex (MHC) class II antigens expressed on antigen-activated human CD4+ T-lymphocytes induces early signal transduction events including the activation of tyrosine kinases, the tyrosine phosphorylation of phospholipase-C gamma 1 and the mobilization of intracellular calcium. Similar responses have been observed in B-cells following stimulation of MHC class II molecules, including the increased production of intracellular cAMP. In this report, we demonstrate that the ZAP-70 tyrosine kinase is a responsive signaling element following cross-linking of HLA-DR in class II+ T-cells, and that the homologous tyrosine kinase p72syk is stimulated in B-cells following ligation of class II antigens. Antibody mediated co-ligation of the T-cell antigen receptor (TCR/CD3) with class II molecules resulted in augmented tyrosine phosphorylation of ZAP-70. Comparable to antibody induced receptor ligation, bacterial superantigen (SEA and SEB) treatment of HLA-DR+ T-cells stimulated ZAP-70 tyrosine phosphorylation, consistent with class II transmembrane signaling by ligation of HLA-DR and V beta in cis. Modulation of the TCR/CD3 led to abrogation of class II induced ZAP-70 tyrosine phosphorylation, but did not result in sequestering of ZAP-70 from the cellular cytoplasm. Hyperphosphorylated ZAP-70 was associated with TCR/CD3 zeta-chain following cross-linking of HLA-DR, suggesting a mechanism for the TCR/CD3-dependence of class II induced signals in alloantigen-activated human T-cells. In both tonsillar B-lymphocytes and B-cell leukemia lines, p72syk was rapidly phosphorylated on tyrosine residues following HLA-DR cross-linking. Tyrosine phosphorylation of p72syk induced through ligation of either the B-cell antigen receptor or class II molecules was potently inhibited by herbimycin A. MHC class II ligation on B-lymphocytes resulted in cell death, which was both qualitatively distinct from Fas-induced apoptosis and partially protected by herbimycin A pretreatment. Thus, ligation of MHC class II molecules expressed on human lymphocytes stimulates the ZAP-70/p72syk family of tyrosine kinases, leading functionally to a tyrosine kinase-dependent pathway of receptor-induced cell death.
AB - Ligation of major histocompatibility complex (MHC) class II antigens expressed on antigen-activated human CD4+ T-lymphocytes induces early signal transduction events including the activation of tyrosine kinases, the tyrosine phosphorylation of phospholipase-C gamma 1 and the mobilization of intracellular calcium. Similar responses have been observed in B-cells following stimulation of MHC class II molecules, including the increased production of intracellular cAMP. In this report, we demonstrate that the ZAP-70 tyrosine kinase is a responsive signaling element following cross-linking of HLA-DR in class II+ T-cells, and that the homologous tyrosine kinase p72syk is stimulated in B-cells following ligation of class II antigens. Antibody mediated co-ligation of the T-cell antigen receptor (TCR/CD3) with class II molecules resulted in augmented tyrosine phosphorylation of ZAP-70. Comparable to antibody induced receptor ligation, bacterial superantigen (SEA and SEB) treatment of HLA-DR+ T-cells stimulated ZAP-70 tyrosine phosphorylation, consistent with class II transmembrane signaling by ligation of HLA-DR and V beta in cis. Modulation of the TCR/CD3 led to abrogation of class II induced ZAP-70 tyrosine phosphorylation, but did not result in sequestering of ZAP-70 from the cellular cytoplasm. Hyperphosphorylated ZAP-70 was associated with TCR/CD3 zeta-chain following cross-linking of HLA-DR, suggesting a mechanism for the TCR/CD3-dependence of class II induced signals in alloantigen-activated human T-cells. In both tonsillar B-lymphocytes and B-cell leukemia lines, p72syk was rapidly phosphorylated on tyrosine residues following HLA-DR cross-linking. Tyrosine phosphorylation of p72syk induced through ligation of either the B-cell antigen receptor or class II molecules was potently inhibited by herbimycin A. MHC class II ligation on B-lymphocytes resulted in cell death, which was both qualitatively distinct from Fas-induced apoptosis and partially protected by herbimycin A pretreatment. Thus, ligation of MHC class II molecules expressed on human lymphocytes stimulates the ZAP-70/p72syk family of tyrosine kinases, leading functionally to a tyrosine kinase-dependent pathway of receptor-induced cell death.
M3 - Journal article
C2 - 8525473
SN - 2059-2302
VL - 46
SP - 145
EP - 154
JO - HLA
JF - HLA
IS - 3 ( Pt 1)
ER -