Signaling Life and Death in the Thymus: Timing Is Everything

T lymphocytes are generated in the thymus, where developing thymocytes must accept one of two fates: They either differentiate or they die. These fates are chiefly determined by signals that originate from the T cell receptor (TCR), a single receptor complex with a remarkable capacity to decide between distinct cell fates. This review explores TCR signaling in thymocytes and focuses on the kinetic aspects of ligand binding, coreceptor involvement, protein phosphorylation, and mitogen-activated protein kinase (MAPK) activation. Understanding the logic of TCR signaling may eventually explain how thymocytes and T cells distinguish self from nonself, a phenomenon that has fascinated immunologists for 50 years.

[1]  J. Stone,et al.  RasGRP1 transduces low-grade TCR signals which are critical for T cell development, homeostasis, and differentiation. , 2002, Immunity.

[2]  E. Palmer,et al.  A Role for the α-Chain Connecting Peptide Motif in Mediating TCR-CD8 Cooperation , 2002, The Journal of Immunology.

[3]  Stuart M. Brown,et al.  Rare, structurally homologous self-peptides promote thymocyte positive selection. , 2002, Immunity.

[4]  H. Kessels,et al.  Contributions of the T Cell Receptor–associated CD3γ–ITAM to Thymocyte Selection , 2002, The Journal of experimental medicine.

[5]  B. Malissen,et al.  Induction of T Helper Type 2 Immunity by a Point Mutation in the LAT Adaptor , 2002, Science.

[6]  L. Samelson,et al.  A LAT Mutation That Inhibits T Cell Development Yet Induces Lymphoproliferation , 2002, Science.

[7]  P. Love,et al.  Distinct Structure and Signaling Potential of the γδTCR Complex , 2002 .

[8]  E. Palmer,et al.  The T-cell receptor signalosome: a dynamic structure with expanding complexity. , 2002, Current opinion in immunology.

[9]  I. Mérida,et al.  Expression of a catalytically inactive form of diacylglycerol kinase α induces sustained signaling through RasGRP , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  A. Singer,et al.  New perspectives on a developmental dilemma: the kinetic signaling model and the importance of signal duration for the CD4/CD8 lineage decision. , 2002, Current opinion in immunology.

[11]  Yun-Cai Liu,et al.  Cbl and Cbl-b in T-cell regulation. , 2002, Trends in immunology.

[12]  A. Strasser,et al.  BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes , 2002, Nature.

[13]  J. Altman,et al.  CD8 binding to MHC class I molecules is influenced by T cell maturation and glycosylation. , 2001, Immunity.

[14]  B. Freedman,et al.  Differential requirement for SLP-76 domains in T cell development and function. , 2001, Immunity.

[15]  E. Reinherz,et al.  Developmentally Regulated Glycosylation of the CD8αβ Coreceptor Stalk Modulates Ligand Binding , 2001, Cell.

[16]  Pamela S. Ohashi,et al.  Duration and Strength of Extracellular Signal-Regulated Kinase Signals Are Altered During Positive Versus Negative Thymocyte Selection1 , 2001, The Journal of Immunology.

[17]  S. Ishii,et al.  Murine Schnurri-2 is required for positive selection of thymocytes , 2001, Nature Immunology.

[18]  A. Weiss,et al.  The Src-like adaptor protein downregulates the T cell receptor on CD4+CD8+ thymocytes and regulates positive selection. , 2001, Immunity.

[19]  A. Weiss,et al.  Identification of the Minimal Tyrosine Residues Required for Linker for Activation of T Cell Function* , 2001, The Journal of Biological Chemistry.

[20]  P. Paz,et al.  Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells. , 2001, The Biochemical journal.

[21]  A. Cheng,et al.  Requirement for the SLP-76 Adaptor GADS in T Cell Development , 2001, Science.

[22]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.

[23]  C. Murre,et al.  Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade , 2001, Nature Immunology.

[24]  T. Pawson,et al.  Disruption of T cell signaling networks and development by Grb2 haploid insufficiency , 2001, Nature Immunology.

[25]  J. Stone,et al.  RasGRP is essential for mouse thymocyte differentiation and TCR signaling , 2000, Nature Immunology.

[26]  B. Alarcón,et al.  CD3δ couples T-cell receptor signalling to ERK activation and thymocyte positive selection , 2000, Nature.

[27]  Barbara Hausmann,et al.  A motif in the αβ T-cell receptor controls positive selection by modulating ERK activity , 2000, Nature.

[28]  P. Love,et al.  ITAM multiplicity and thymocyte selection: how low can you go? , 2000, Immunity.

[29]  S. Sakaguchi.  Regulatory T cells , 2006, Springer Seminars in Immunopathology.

[30]  D. Kioussis,et al.  Inducible expression of a p56Lck transgene reveals a central role for Lck in the differentiation of CD4 SP thymocytes. , 2000, Immunity.

[31]  J. Alberola-Ila,et al.  Lck activity controls CD4/CD8 T cell lineage commitment. , 2000, Immunity.

[32]  A. Smolyar,et al.  The crystal structure of a T cell receptor in complex with peptide and MHC class II. , 1999, Science.

[33]  S. R. Datta,et al.  Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. , 1999, Science.

[34]  S. Jameson,et al.  Qualitative and quantitative differences in T cell receptor binding of agonist and antagonist ligands. , 1999, Immunity.

[35]  D. Kioussis,et al.  Bad Can Act as a Key Regulator of  T Cell Apoptosis and T Cell Development , 1999, The Journal of experimental medicine.

[36]  K. Garcia,et al.  Structural basis of T cell recognition. , 1999, Annual review of immunology.

[37]  M. Naramura,et al.  Altered thymic positive selection and intracellular signals in Cbl-deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  E. Palmer,et al.  Positive Selection Through a Motif in the αβ T Cell Receptor , 1998 .

[39]  J. Stone,et al.  RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. , 1998, Science.

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

[41]  H. Fehling,et al.  Molecular and cellular events in early thymocyte development. , 1998, Advances in immunology.

[42]  F. Lemonnier,et al.  Differential requirements for survival and proliferation of CD8 naïve or memory T cells. , 1997, Science.

[43]  S. Tonegawa,et al.  CD3δ deficiency arrests development of the αβ but not the γδ T cell lineage , 1997 .

[44]  J. Exton.  Cell signalling through guanine-nucleotide-binding regulatory proteins (G proteins) and phospholipases. , 1997, European journal of biochemistry.

[45]  E. Palmer,et al.  A motif within the T cell receptor alpha chain constant region connecting peptide domain controls antigen responsiveness. , 1996, Immunity.

[46]  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.

[47]  S. Jameson,et al.  T-cell-receptor affinity and thymocyte positive selection , 1996, Nature.

[48]  M. Greenberg,et al.  E2F-1 Functions in Mice to Promote Apoptosis and Suppress Proliferation , 1996, Cell.

[49]  C. Janeway.  Immunobiology: The Immune System in Health and Disease , 1996 .

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

[51]  M. Bevan,et al.  Strong agonist ligands for the T cell receptor do not mediate positive selection of functional CD8+ T cells. , 1995, Immunity.

[52]  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.

[53]  A. Lanzavecchia,et al.  Serial triggering of many T-cell receptors by a few peptide–MHC complexes , 1995, Nature.

[54]  C. Marshall,et al.  Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation , 1995, Cell.

[55]  P. Romero,et al.  CD8 modulation of T-cell antigen receptor–ligand interactions on living cytotoxic T lymphocytes , 1995, Nature.

[56]  P. Fink,et al.  Positive selection of thymocytes. , 1995, Annual review of immunology.

[57]  P. Ohashi,et al.  Positive and negative thymocyte selection induced by different concentrations of a single peptide. , 1994, Science.

[58]  S. Tonegawa,et al.  Evidence for a differential avidity model of T cell selection in the thymus , 1994, Cell.

[59]  C. Walsh,et al.  Phosphorylation of Ser-42 and Ser-59 in the N-terminal region of the tyrosine kinase p56lck. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[60]  H. Pircher,et al.  CD8 is needed for positive selection but differentially required for negative selection of T cells during thymic ontogeny , 1993, European journal of immunology.

[61]  H. von Boehmer,et al.  The thymus selects the useful, neglects the useless and destroys the harmful. , 1989, Immunology today.

[62]  J. Bluestone,et al.  Substitution at residue 227 of H–2 class I molecules abrogates recognition by CD8-dependent, but not CD8-independent, cytotoxic T lymphocytes , 1989, Nature.

[63]  Michael A. Bookman,et al.  The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56 lck , 1988, Cell.

[64]  J. Strominger,et al.  Interaction between CD4 and class II MHC molecules mediates cell adhesion , 1987, Nature.

[65]  R. Zinkernagel,et al.  Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system , 1974, Nature.