Alternative Antigen Receptor (TCR) Signaling in T Cells Derived from ZAP-70-deficient Patients Expressing High Levels of Syk*

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 Sykhi/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-γ1), as well as calcium mobilization, which are defective in T cells expressing neither ZAP-70 nor Syk, are observed in Sykhi/ZAP-70− T cells. However, Sykhi/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 Sykhi/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.

[1]  S. Matsuda,et al.  Temperature-sensitive ZAP70 Mutants Degrading through a Proteasome-independent Pathway , 1999, The Journal of Biological Chemistry.

[2]  A. Singer,et al.  Association of the Adaptor Molecule Lat with Cd4 and Cd8 Coreceptors Identifies a New Coreceptor Function in T Cell Receptor Signal Transduction , 1999, The Journal of experimental medicine.

[3]  Hii,et al.  Direct evidence that ERK regulates the production/secretion of interleukin‐2 in PHA/PMA‐stimulated T lymphocytes , 1999, Immunology.

[4]  P. Besmer,et al.  Kit signaling through PI 3‐kinase and Src kinase pathways: an essential role for Rac1 and JNK activation in mast cell proliferation , 1998, The EMBO journal.

[5]  A. Weiss,et al.  The Syk family of protein tyrosine kinases in T‐cell activation and development , 1998, Immunological reviews.

[6]  E. Nishida,et al.  T Lymphocyte Activation Signals for Interleukin-2 Production Involve Activation of MKK6-p38 and MKK7-SAPK/JNK Signaling Pathways Sensitive to Cyclosporin A* , 1998, The Journal of Biological Chemistry.

[7]  J. Tschopp,et al.  Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. , 1998, Immunity.

[8]  R. Abraham,et al.  Genetic Evidence for Differential Coupling of Syk Family Kinases to the T-Cell Receptor: Reconstitution Studies in a ZAP-70-Deficient Jurkat T-Cell Line , 1998, Molecular and Cellular Biology.

[9]  L. Samelson,et al.  LAT The ZAP-70 Tyrosine Kinase Substrate that Links T Cell Receptor to Cellular Activation , 1998, Cell.

[10]  M. Karin,et al.  Cooperation between Syk and Rac1 leads to synergistic JNK activation in T lymphocytes. , 1998, Immunity.

[11]  Tetsuya Nakamura,et al.  The Igα/Igβ Heterodimer on μ-Negative ProB Cells Is Competent for Transducing Signals to Induce Early B Cell Differentiation , 1997 .

[12]  A. Chan,et al.  Restoration of thymocyte development and function in zap-70-/- mice by the Syk protein tyrosine kinase. , 1997, Immunity.

[13]  S. Latour,et al.  Regulation of T-cell antigen receptor signalling by Syk tyrosine protein kinase , 1997, Molecular and cellular biology.

[14]  D. Singer,et al.  A spontaneously arising mutation in the DLAARN motif of murine ZAP-70 abrogates kinase activity and arrests thymocyte development. , 1997, Immunity.

[15]  Christopher C. Goodnow,et al.  Differential activation of transcription factors induced by Ca2+ response amplitude and duration , 1997, Nature.

[16]  F. Alt,et al.  Functional responses and apoptosis of CD25 (IL-2R alpha)-deficient T cells expressing a transgenic antigen receptor. , 1997, Journal of immunology.

[17]  N. Taylor,et al.  Differential Activation of the Tyrosine Kinases ZAP-70 and Syk After FcγRI Stimulation , 1997 .

[18]  A. Weiss,et al.  The Syk protein tyrosine kinase can function independently of CD45 or Lck in T cell antigen receptor signaling. , 1996, The EMBO journal.

[19]  A. Veillette,et al.  Differential Intrinsic Enzymatic Activity of Syk and Zap-70 Protein-tyrosine Kinases* , 1996, The Journal of Biological Chemistry.

[20]  I. Macara,et al.  JNK, but not MAPK, activation is associated with Fas‐mediated apoptosis in human T cells , 1996, European journal of immunology.

[21]  N. Taylor,et al.  Correction of interleukin-2 receptor function in X-SCID lymphoblastoid cells by retrovirally mediated transfer of the gamma-c gene. , 1996, Blood.

[22]  H. Reiser,et al.  Activation of CD4+ T lymphocytes form interleukin 2-deficient mice by costimulatory B7 molecules. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  D. Cantrell,et al.  T cell antigen receptor signal transduction pathways. , 1996, Annual review of immunology.

[24]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[25]  K. Weinberg,et al.  Absence of ZAP-70 prevents signaling through the antigen receptor on peripheral blood T cells but not on thymocytes , 1995, The Journal of experimental medicine.

[26]  K. Nakayama,et al.  Essential role for ZAP-70 in both positive and negative selection of thymocytes , 1995, Nature.

[27]  D. Cantrell,et al.  The regulation and function of p21ras during T-cell activation and growth. , 1995, Immunology today.

[28]  G L Johnson,et al.  Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. , 1994, Science.

[29]  T. Hope,et al.  Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. , 1994, Science.

[30]  W. Kuo,et al.  ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. , 1994, Science.

[31]  T. Mustelin,et al.  p56lck-independent activation and tyrosine phosphorylation of p72syk by T-cell antigen receptor/CD3 stimulation. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Masahiko Hibi,et al.  JNK is involved in signal integration during costimulation of T lymphocytes , 1994, Cell.

[33]  A. Weiss,et al.  Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of protein tyrosine kinases in TCR signaling. , 1994, Journal of immunology.

[34]  A. Cohen,et al.  Defective T cell receptor signaling and CD8+ thymic selection in humans lacking Zap-70 kinase , 1994, Cell.

[35]  B. Seed,et al.  T cell activation by clustered tyrosine kinases , 1993, Cell.

[36]  Arthur Weiss,et al.  ZAP-70: A 70 kd protein-tyrosine kinase that associates with the TCR ζ chain , 1992, Cell.

[37]  I. Horak,et al.  Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting , 1991, Nature.

[38]  R. Geha,et al.  Recombinant interleukin 2 therapy in severe combined immunodeficiency disease. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[39]  W. V. van Blitterswijk,et al.  Serum-free medium for generation and propagation of functional human cytotoxic and helper T cell clones. , 1984, Journal of immunological methods.

[40]  J. D. de Vries,et al.  Establishment of human T lymphocyte clones highly cytotoxic for an EBV-transformed B cell line in serum-free medium: isolation of clones that differ in phenotype and specificity. , 1982, Journal of immunology.