Receptor Avidity and Costimulation Specify the Intracellular Ca2+ Signaling Pattern in Cd4+Cd8+ Thymocytes

Thymocyte maturation is governed by antigen–T cell receptor (TCR) affinity and the extent of TCR aggregation. Signals provided by coactivating molecules such as CD4 and CD28 also influence the fate of immature thymocytes. The mechanism by which differences in antigen–TCR avidity encode unique maturational responses of lymphocytes and the influence of coactivating molecules on these signaling processes is not fully understood. To better understand the role of a key second messenger, calcium, in governing thymocyte maturation, we measured the intracellular free calcium concentration ([Ca2+] i) response to changes in TCR avidity and costimulation. We found that TCR stimulation initiates either amplitude- or frequency-encoded [Ca2+]i changes depending on (a) the maturation state of stimulated thymocytes, (b) the avidity of TCR interactions, and (c) the participation of specific coactivating molecules. Calcium signaling within immature but not mature thymocytes could be modulated by the avidity of CD3/CD4 engagement. Low avidity interactions induced biphasic calcium responses, whereas high avidity engagement initiated oscillatory calcium changes. Notably, CD28 participation converted the calcium response to low avidity receptor engagement from a biphasic to oscillatory pattern. These data suggest that calcium plays a central role in encoding the nature of the TCR signal received by thymocytes and, consequently, a role in thymic selection.

[1]  M. Hohenegger,et al.  Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose , 1999, Nature.

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

[3]  A. Grinberg,et al.  CD5 Expression Is Developmentally Regulated By T Cell Receptor (TCR) Signals and TCR Avidity , 1998, The Journal of experimental medicine.

[4]  M. Davis,et al.  A receptor/cytoskeletal movement triggered by costimulation during T cell activation. , 1998, Science.

[5]  M. Bachmann,et al.  Degree of TCR internalization and Ca2+ flux correlates with thymocyte selection. , 1998, Journal of immunology.

[6]  Tobias Meyer,et al.  Protein Kinase C as a Molecular Machine for Decoding Calcium and Diacylglycerol Signals , 1998, Cell.

[7]  R. Boyd,et al.  Positive selection of low responsive, potentially autoreactive T cells induced by high avidity, non-deleting interactions. , 1998, International immunology.

[8]  J. Sprent,et al.  A Role for Fas in Negative Selection of Thymocytes In Vivo , 1998, The Journal of experimental medicine.

[9]  Keli Xu,et al.  Calcium oscillations increase the efficiency and specificity of gene expression , 1998, Nature.

[10]  Roger Y. Tsien,et al.  Cell-permeant caged InsP3 ester shows that Ca2+ spike frequency can optimize gene expression , 1998, Nature.

[11]  P. De Koninck,et al.  Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. , 1998, Science.

[12]  M. Hoth,et al.  Mitochondrial Regulation of Store-operated Calcium Signaling in T Lymphocytes , 1997, The Journal of cell biology.

[13]  U. Bommhardt,et al.  Signals through CD8 or CD4 can induce commitment to the CD4 lineage in the thymus , 1997, European journal of immunology.

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

[15]  S. Launay,et al.  Modulation of Endoplasmic Reticulum Calcium Pump Expression during T Lymphocyte Activation* , 1997, The Journal of Biological Chemistry.

[16]  G. Crabtree,et al.  Different nuclear signals are activated by the B cell receptor during positive versus negative signaling. , 1997, Immunity.

[17]  K. S. Dash,et al.  Surface molecules that drive T cell development in vitro in the absence of thymic epithelium and in the absence of lineage-specific signals. , 1997, Immunity.

[18]  G. Dupuis,et al.  A caffeine/ryanodine-sensitive Ca2+ pool is involved in triggering spontaneous variations of Ca2+ in Jurkat T lymphocytes by a Ca(2+)-induced Ca2+ release (CICR) mechanism. , 1997, Cellular signalling.

[19]  J. Sprent,et al.  Negative Selection in the Thymus Includes Semimature T Cells , 1997, The Journal of experimental medicine.

[20]  A. Kruisbeek,et al.  CD28-B7 interactions function to co-stimulate clonal deletion of double-positive thymocytes. , 1996, International immunology.

[21]  S. Ward.  CD28: a signalling perspective. , 1996, The Biochemical journal.

[22]  M. Jackson,et al.  Differing roles for B7 and intercellular adhesion molecule-1 in negative selection of thymocytes , 1996, The Journal of experimental medicine.

[23]  S. Hedrick,et al.  A role for calcium influx in setting the threshold for CD4+CD8+ thymocyte negative selection. , 1996, Journal of immunology.

[24]  H. Vijverberg,et al.  Intracellular Ca2+ oscillations and membrane potential fluctuations in intact human T lymphocytes: role of K+ channels in Ca2+ signaling. , 1995, Cell calcium.

[25]  K. Resch,et al.  T-cell antigen receptor-induced signal-transduction pathways Activation and function of protein kinases C in T lymphocytes , 1995 .

[26]  R. Lewis,et al.  Rapid inactivation of depletion-activated calcium current (ICRAC) due to local calcium feedback , 1995, The Journal of general physiology.

[27]  K. Katz,et al.  Positive selection of CD4+ T cells by TCR ligation without aggregation even in the absence of MHC , 1994, Nature.

[28]  S. Tonegawa,et al.  A differential-avidity model for T-cell selection. , 1994, Immunology today.

[29]  P. Negulescu,et al.  Intracellular calcium dependence of gene expression in single T lymphocytes. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

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

[31]  H. Korn,et al.  Different patterns of calcium signaling triggered through two components of the B lymphocyte antigen receptor. , 1994, The Journal of biological chemistry.

[32]  R. Dolmetsch,et al.  Signaling between intracellular Ca2+ stores and depletion-activated Ca2+ channels generates [Ca2+]i oscillations in T lymphocytes , 1994, The Journal of general physiology.

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

[34]  A. Singer,et al.  Negative selection of CD4+CD8+ thymocytes by T cell receptor-induced apoptosis requires a costimulatory signal that can be provided by CD28 , 1994, The Journal of experimental medicine.

[35]  R. Klausner,et al.  Regulation of T cell receptor expression in immature CD4+CD8+ thymocytes by p56lck tyrosine kinase: basis for differential signaling by CD4 and CD8 in immature thymocytes expressing both coreceptor molecules , 1993, The Journal of experimental medicine.

[36]  A. Velardi,et al.  Antibodies to CD44 trigger effector functions of human T cell clones. , 1993, Journal of immunology.

[37]  M. Cahalan,et al.  Calcium oscillations in human T and natural killer cells depend upon membrane potential and calcium influx. , 1993, Journal of immunology.

[38]  R. Abe,et al.  T cell receptor-mediated recognition of self-ligand induces signaling in immature thymocytes before negative selection , 1992, The Journal of experimental medicine.

[39]  R. Sékaly,et al.  Association of tyrosine kinase p56lck with CD4 inhibits the induction of growth through the αβ T-cell receptor , 1992, Nature.

[40]  C. June,et al.  In vivo calcium elevations in thymocytes with T cell receptors that are specific for self ligands. , 1992, Science.

[41]  Arthur Weiss,et al.  The role of protein kinase C in transmembrane signaling by the T cell antigen receptor complex. Effects of stimulation with soluble or immobilized CD3 antibodies. , 1987, Journal of immunology.

[42]  R. Tsien,et al.  A new generation of Ca2+ indicators with greatly improved fluorescence properties. , 1985, The Journal of biological chemistry.

[43]  B. Motyka,et al.  Influence of the affinity of selecting ligands on T cell positive and negative selection and the functional maturity of the positively selected T cells. , 1997, Critical reviews in immunology.

[44]  R. Dolmetsch,et al.  Positive and negative regulation of depletion-activated calcium channels by calcium. , 1996, Society of General Physiologists series.

[45]  K. Resch,et al.  T-cell antigen receptor-induced signal-transduction pathways--activation and function of protein kinases C in T lymphocytes. , 1995, European journal of biochemistry.

[46]  R. Sékaly,et al.  Association of tyrosine kinase p56lck with CD4 inhibits the induction of growth through the alpha beta T-cell receptor. , 1992, Nature.