Differential requirements for NF-kappaB and AP-1 trans-activation in response to minimal TCR engagement by a partial agonist in naive CD8 T cells.

We investigated the basis for partial reactivity of naive CD8 T cells expressing an alloreactive transgenic TCR in response to a mutant alloantigen. When unstimulated APCs were used, IFN-gamma as well as IL-2 and cell proliferation were observed in response to wild-type Ag, whereas mutant Ag induced only IFN-gamma. DNA binding and reporter gene assays showed that the response to mutant Ag involved NF-kappaB, but not AP-1 activation, whereas wild-type Ag activated both transcription factors. Increasing the contribution of costimulatory signals by using LPS-activated APCs partially corrected the activation by mutant Ag, because proliferation and weak IL-2 production could be measured. This also led to AP-1 activation, albeit with delayed kinetics, in response to mutant Ag. To explain how engagement of the same TCR by distinct ligands results in different T cell responses, it may be proposed, in line with models stressing the importance of the kinetics of Ag/TCR interaction, that two types of signals be distinguished: a "fast" short-lived signal is sufficient to activate NF-kappaB; whereas a "slow" signal obtained after prolonged TCR engagement is required for AP-1 activation. Failure to activate AP-1 in limiting conditions (unstimulated mutant APC) was partially corrected by increasing costimulation.

[1]  W. Greene,et al.  The Proto-Oncogene Cot Kinase Participates in CD3/CD28 Induction of NF-κB Acting through the NF-κB-Inducing Kinase and IκB Kinases , 1999 .

[2]  A. Lanzavecchia,et al.  T lymphocyte costimulation mediated by reorganization of membrane microdomains. , 1999, Science.

[3]  M. Mescher,et al.  ICAM‐1 and B7‐1 provide similar but distinct costimulation for CD8+ T cells, while CD4+ T cells are poorly costimulated by ICAM‐1 , 1999, European journal of immunology.

[4]  Graham M Lord,et al.  A kinetic differentiation model for the action of altered TCR ligands. , 1999, Immunology today.

[5]  A. Sundstedt,et al.  In vivo anergized CD4+ T cells have defective expression and function of the activating protein-1 transcription factor. , 1998, Journal of immunology.

[6]  H. Kohler,et al.  Partial agonism and independent modulation of T cell receptor and CD8 in hapten‐specific cytotoxic T cells , 1998, European journal of immunology.

[7]  P. Allen,et al.  Fidelity of T cell activation through multistep T cell receptor zeta phosphorylation. , 1998, Science.

[8]  L. Tuosto,et al.  CD28 affects the earliest signaling events generated by TCR engagement , 1998, European journal of immunology.

[9]  M. Karin,et al.  Stabilization of interleukin-2 mRNA by the c-Jun NH2-terminal kinase pathway. , 1998, Science.

[10]  R. Flavell,et al.  Consequences of intrathymic TCR engagement by partial agonist on selection events and peripheral T cell activation program. , 1998, Journal of immunology.

[11]  P. Klenerman,et al.  Copresentation of natural HIV-1 agonist and antagonist ligands fails to induce the T cell receptor signaling cascade. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  S. Ghosh,et al.  Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. , 1998, Molecular cell.

[13]  P. Baeuerle Pro-inflammatory signaling: Last pieces in the NF-κB puzzle? , 1998, Current Biology.

[14]  B. Nelson,et al.  Biology of the interleukin-2 receptor. , 1998, Advances in immunology.

[15]  D. Hudrisier,et al.  Role of CD8 in Aberrant Function of Cytotoxic T Lymphocytes , 1997, The Journal of experimental medicine.

[16]  E. Lara-Pezzi,et al.  Expression of the leukocyte early activation antigen CD69 is regulated by the transcription factor AP-1. , 1997, Journal of immunology.

[17]  T. Mak,et al.  Distinct roles for LFA-1 and CD28 during activation of naive T cells: adhesion versus costimulation. , 1997, Immunity.

[18]  R. Zinkernagel,et al.  Peptide‐induced T cell receptor down‐regulation on naive T cells predicts agonist/partial agonist properties and strictly correlates with T cell activation , 1997, European journal of immunology.

[19]  R. Germain,et al.  Single Cell Analysis Reveals Regulated Hierarchical T Cell Antigen Receptor Signaling Thresholds and Intraclonal Heterogeneity for Individual Cytokine Responses of CD4+ T Cells , 1997, The Journal of experimental medicine.

[20]  T. Preckel,et al.  Altered Hapten Ligands Antagonize Trinitrophenyl-specific Cytotoxic T Cells and Block Internalization of Hapten-specific Receptors , 1997, The Journal of experimental medicine.

[21]  E. Zandi,et al.  AP-1 function and regulation. , 1997, Current opinion in cell biology.

[22]  M. Jackson,et al.  Requirements for Peptide-induced T Cell Receptor Downregulation on Naive CD8+ T Cells , 1997, The Journal of experimental medicine.

[23]  B. Ozanne,et al.  AP-1-mediated invasion requires increased expression of the hyaluronan receptor CD44 , 1997, Molecular and cellular biology.

[24]  R. Germain,et al.  The Efficiency of CD4 Recruitment to Ligand-engaged TCR Controls the Agonist/Partial Agonist Properties of Peptide–MHC Molecule Ligands , 1997, The Journal of experimental medicine.

[25]  M. Jackson,et al.  Transfected Drosophila cells as a probe for defining the minimal requirements for stimulating unprimed CD8+ T cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[26]  P. Romero,et al.  CD8β Increases CD8 Coreceptor Function and Participation in TCR–Ligand Binding , 1996, The Journal of experimental medicine.

[27]  Partho Ghosh,et al.  Structure of the complex between human T-cell receptor, viral peptide and HLA-A2 , 1996, Nature.

[28]  Robyn L. Stanfield,et al.  An αβ T Cell Receptor Structure at 2.5 Å and Its Orientation in the TCR-MHC Complex , 1996, Science.

[29]  A. Simon,et al.  Developmental control of antigen-induced thymic transcription factors. , 1996, International immunology.

[30]  M. Jenkins,et al.  Defective transcription of the IL-2 gene is associated with impaired expression of c-Fos, FosB, and JunB in anergic T helper 1 cells. , 1996, Journal of immunology.

[31]  Antonio Lanzavecchia,et al.  T Cell Activation Determined by T Cell Receptor Number and Tunable Thresholds , 1996, Science.

[32]  Y. Chien,et al.  A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists. , 1996, Immunity.

[33]  M. Bevan,et al.  Selective activation of Fas/Fas ligand-mediated cytotoxicity by a self peptide , 1996, The Journal of experimental medicine.

[34]  M. Davis,et al.  Kinetic discrimination in T-cell activation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[35]  T. Braciale,et al.  Partial activation of CD8+ T cells by a self-derived peptide , 1995, Nature.

[36]  Joseph A. DiDonato,et al.  Immunosuppression by Glucocorticoids: Inhibition of NF-κB Activity Through Induction of IκB Synthesis , 1995, Science.

[37]  J. Rothbard,et al.  Specific T cell recognition of minimally homologous peptides: evidence for multiple endogenous ligands. , 1995, Immunity.

[38]  T. McKeithan,et al.  Kinetic proofreading in T-cell receptor signal transduction. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[39]  L. Samelson,et al.  Zeta phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists , 1995, Science.

[40]  Paul M. Allen,et al.  Partial T cell signaling: Altered phospho-ζ and lack of zap70 recruitment in APL-induced T cell anergy , 1994, Cell.

[41]  R. Flavell,et al.  AP‐1 transcriptional activity requires both T‐cell receptor‐mediated and co‐stimulatory signals in primary T lymphocytes. , 1994, The EMBO journal.

[42]  J. Curnow,et al.  The degree of CD8 dependence of cytolytic T cell precursors is determined by the nature of the T cell receptor (TCR) and influences negative selection in TCR‐transgenic mice , 1994, European journal of immunology.

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

[44]  A. B. Lyons,et al.  Determination of lymphocyte division by flow cytometry. , 1994, Journal of immunological methods.

[45]  M. Karin,et al.  JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain , 1994, Cell.

[46]  P. Allen,et al.  Tickling the TCR: selective T-cell functions stimulated by altered peptide ligands. , 1993, Immunology today.

[47]  P. Linsley,et al.  Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. , 1993, Science.

[48]  A. Lanzavecchia,et al.  Expression and functional properties of mouse B7/BB1 using a fusion protein between mouse CTLA4 and human gamma 1. , 1993, Immunology.

[49]  M. Bevan,et al.  Clone-specific T cell receptor antagonists of major histocompatibility complex class I-restricted cytotoxic T cells , 1993, The Journal of experimental medicine.

[50]  P. Allen,et al.  Induction of T-cell anergy by altered T-cell-receptor ligand on live antigen-presenting cells , 1993, Nature.

[51]  G. Schönrich,et al.  Threshold tolerance in H-2Kb-specific TCR transgenic mice expressing mutant H-2Kb: conversion of helper-independent to helper-dependent CTL. , 1992, International immunology.

[52]  K. Brorson,et al.  Transactivation by AP-1 Is a Molecular Target of T Cell Clonal Anergy , 1992, Science.

[53]  B. Malissen,et al.  Role of CD3 delta in surface expression of the TCR/CD3 complex and in activation for killing analyzed with a CD3 delta-negative cytotoxic T lymphocyte variant. , 1992, Journal of immunology.

[54]  S. Nathenson,et al.  The structure of the antigen-binding groove of major histocompatibility complex class I molecules determines specific selection of self-peptides. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[55]  P. Allen,et al.  Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand. , 1991, Science.

[56]  V. Moy,et al.  The accessory function of murine intercellular adhesion molecule-1 in T lymphocyte activation. Contributions of adhesion and co-activation. , 1991, Journal of immunology.

[57]  G. Crabtree,et al.  Transmission of signals from the T lymphocyte antigen receptor to the genes responsible for cell proliferation and immune function: the missing link. , 1990, Annual review of immunology.

[58]  R. Schwartz,et al.  T-cell clonal anergy. , 1997, Cold Spring Harbor symposia on quantitative biology.

[59]  J. Coligan,et al.  Characterization of a cell surface-expressed disulfide-linked dimer involved in murine T cell activation. , 1988, Journal of immunology.

[60]  A. McMichael,et al.  The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides , 1986, Cell.

[61]  Z. Eshhar,et al.  Lymphoid Cell Surface Interaction Structures Detected Using Cytolysis‐Inhibiting Monoclonal Antibodies , 1982, Immunological reviews.