Alternative antigen receptor (TCR) signaling in T cells derived from ZAP-70-deficient patients expressing high levels of Syk

N. Noraz , K. Schwarz , M. Steinberg , V. Dardalhon (1) , C. Rebouissou , R. Hipskind , W. Friedrich , H. Yssel , K. Bacon , N. Taylor (1)

1 IGMM - Institut de Génétique Moléculaire de Montpellier

ZAP-70-deficient patients present with nonfunctional CD4+ T cells in the periphery. We find that a subset of primary ZAP-70-deficient T cells, expressing high levels of the related protein-tyrosine kinase Syk, can proliferate in vitro. These cells (denoted herein as Syk(hi)/ZAP-70(-) T cells) provide a unique model in which the contribution of Syk to TCR-mediated responses can be explored in a nontransformed background. Importantly, CD3-induced responses, such as tyrosine phosphorylation of cellular substrates (LAT, SLP76, and PLC-gamma1), as well as calcium mobilization, which are defective in T cells expressing neither ZAP-70 nor Syk, are observed in Syk(hi)/ZAP-70(-) T cells. However, Syk(hi)/ZAP-70(-) T cells differ from control T cells with respect to the T cell antigen receptor (TCR)-mediated activation of the MAPK cascades: extracellular signal-regulated kinase activity and recruitment of the JNK and p38 stress-related MAPK pathways are diminished. This distinct phenotype of Syk(hi)/ZAP-70(-) T cells is associated with a profound decrease in CD3-mediated interleukin 2 secretion and proliferation relative to control T cells. Thus, ZAP-70 and Syk appear to play distinct roles in transducing a TCR-mediated signal.

Mots clés: Signal Transducing Antigens; T-Cell/*metabolism Signal Transduction/genetics Type C Phospholipases/metabolism ZAP-70 Protein-Tyrosine Kinase; Antigen; *Adaptor Proteins; CD3/metabolism Base Sequence Calcium/metabolism Carrier Proteins/metabolism Cell Division Enzyme Precursors/*metabolism Humans Interleukin-2/secretion Intracellular Signaling Peptides and Proteins Isoenzymes/metabolism JNK Mitogen-Activated Protein Kinases Jurkat Cells *Membrane Proteins Mitogen-Activated Protein Kinases/metabolism Molecular Sequence Data Mutation Phospholipase C gamma Phosphoproteins/metabolism Phosphorylation Phosphotyrosine/metabolism Protein-Tyrosine Kinases/*deficiency/genetics/*metabolism Receptors

Domaines: Biochimie, Biologie Moléculaire

N. Noraz, K. Schwarz, M. Steinberg, V. Dardalhon, C. Rebouissou, et al.. Alternative antigen receptor (TCR) signaling in T cells derived from ZAP-70-deficient patients expressing high levels of Syk. Journal of Biological Chemistry, 2000, 275 (21), pp.15832--8. ⟨10.1074/jbc.M908568199⟩. ⟨hal-02196824⟩