| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, and
Cellular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892
In the present study, we examined the relationships among
quantitative aspects of TCR engagement as measured by receptor
down-modulation, functional responses, and biochemical signaling events
using both mouse and human T cell clones. For T cells from both
species, ligands that are more potent in inducing functional responses
promote TCR down-modulation more efficiently than weaker ligands. At
low ligand density, the number of down-modulated TCR exceeds the number
of available ligands by as much as 80–100:1 in the optimal human case,
confirming the previous description of serial ligand engagement of TCR
(Valitutti, et al. 1995. Nature 375:148–151). A previously
unappreciated relationship involving TCR down-modulation, the pattern
of proximal TCR signaling, and the extent of serial engagement was
revealed by analyzing different ligands for the same TCR. Functionally,
more potent ligands induce a higher proportion of fully tyrosine
phosphorylated 
-chains and a greater amount of phosphorylated ZAP-70
than less potent ligands, and the number of TCR down-modulated per
available ligand is higher with ligands showing this full agonist-like
pattern. The large number of receptors showing partial
phosphorylation following exposure to weak ligands indicates that the
true extent of TCR engagement and signaling, and thus the amount of
sequential engagement, is underestimated by measurement of TCR
down-modulation alone, which depends on full receptor activation. These
data provide new insight into T cell activation by revealing a clear
relationship among intrinsic ligand quality, signal amplification by
serial engagement, functional T cell responses, and observable TCR
clearance from the cell surface.
This article has been cited by other articles:
|
|
 |
|
  G. Noel, C. Brinster, G. Semana, and D. Bruniquel Modulation of the TCR stimulation strength can render human activated CD4+ T cells suppressive Int. Immunol., September 1, 2009; 21(9): 1025 - 1036. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, X. Chen, L. Rodenkirch, W. Simonson, S. Wernimont, R. M. Ndonye, N. Veerapen, D. Gibson, A. R. Howell, G. S. Besra, et al. Natural killer T-cell autoreactivity leads to a specialized activation state Blood, November 15, 2008; 112(10): 4128 - 4138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T. Chang, J. J. Linderman, and D. E. Kirschner Effect of Multiple Genetic Polymorphisms on Antigen Presentation and Susceptibility to Mycobacterium tuberculosis Infection Infect. Immun., July 1, 2008; 76(7): 3221 - 3232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. James, P. D. Greenberg, M. C. Jensen, Y. Lin, J. Wang, B. G. Till, A. A. Raubitschek, S. J. Forman, and O. W. Press Antigen Sensitivity of CD22-Specific Chimeric TCR Is Modulated by Target Epitope Distance from the Cell Membrane J. Immunol., May 15, 2008; 180(10): 7028 - 7038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hommel and P. D. Hodgkin TCR Affinity Promotes CD8+ T Cell Expansion by Regulating Survival J. Immunol., August 15, 2007; 179(4): 2250 - 2260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Pastor, C. G. Vaccaro, A. Minguela, R. J. Ober, and E. S. Ward Analyses of TCR clustering at the T cell-antigen-presenting cell interface and its impact on the activation of naive CD4+ T cells Int. Immunol., November 1, 2006; 18(11): 1615 - 1625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Lavoie, A. R. Dumont, H. McGrath, A.-E. Kernaleguen, and R.-P. Sekaly Delayed expansion of a restricted T cell repertoire by low-density TCR ligands Int. Immunol., July 1, 2005; 17(7): 931 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Patke and D. L. Farber Modulation of Memory CD4 T Cell Function and Survival Potential by Altering the Strength of the Recall Stimulus J. Immunol., May 1, 2005; 174(9): 5433 - 5443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Munitic, P. E. Ryan, and J. D. Ashwell T Cells in G1 Provide a Memory-Like Response to Secondary Stimulation J. Immunol., April 1, 2005; 174(7): 4010 - 4018. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Gonzalez, L. J. Carreno, D. Coombs, J. E. Mora, E. Palmieri, B. Goldstein, S. G. Nathenson, and A. M. Kalergis T cell receptor binding kinetics required for T cell activation depend on the density of cognate ligand on the antigen-presenting cell PNAS, March 29, 2005; 102(13): 4824 - 4829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. von Essen, C. M. Bonefeld, V. Siersma, A. B. Rasmussen, J. P. H. Lauritsen, B. L. Nielsen, and C. Geisler Constitutive and Ligand-Induced TCR Degradation J. Immunol., July 1, 2004; 173(1): 384 - 393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Betts, D. A. Price, J. M. Brenchley, K. Lore, F. J. Guenaga, A. Smed-Sorensen, D. R. Ambrozak, S. A. Migueles, M. Connors, M. Roederer, et al. The Functional Profile of Primary Human Antiviral CD8+ T Cell Effector Activity Is Dictated by Cognate Peptide Concentration J. Immunol., May 15, 2004; 172(10): 6407 - 6417. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. L. La Gruta, H. Liu, S. Dilioglou, M. Rhodes, D. L. Wiest, and D. A. A. Vignali Architectural Changes in the TCR:CD3 Complex Induced by MHC:Peptide Ligation J. Immunol., March 15, 2004; 172(6): 3662 - 3669. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-H. Lee, A. R. Dinner, C. Tu, G. Campi, S. Raychaudhuri, R. Varma, T. N. Sims, W. R. Burack, H. Wu, J. Wang, et al. The Immunological Synapse Balances T Cell Receptor Signaling and Degradation Science, November 14, 2003; 302(5648): 1218 - 1222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Margalit, S. Fishman, D. Berko, J. Engberg, and G. Gross Chimeric {beta}2 microglobulin/CD3{zeta} polypeptides expressed in T cells convert MHC class I peptide ligands into T cell activation receptors: a potential tool for specific targeting of pathogenic CD8+ T cells Int. Immunol., November 1, 2003; 15(11): 1379 - 1387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Stanic, R. Shashidharamurthy, J. S. Bezbradica, N. Matsuki, Y. Yoshimura, S. Miyake, E. Y. Choi, T. D. Schell, L. Van Kaer, S. S. Tevethia, et al. Another View of T Cell Antigen Recognition: Cooperative Engagement of Glycolipid Antigens by Va14Ja18 Natural TCR J. Immunol., November 1, 2003; 171(9): 4539 - 4551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Hurez, A. Saparov, A. Tousson, M. J. Fuller, T. Kubo, J. Oliver, B. T. Weaver, and C. T. Weaver Restricted Clonal Expression of IL-2 By Naive T Cells Reflects Differential Dynamic Interactions with Dendritic Cells J. Exp. Med., July 7, 2003; 198(1): 123 - 132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Annenkov, G. M. Daly, T. Brocker, and Y. Chernajovsky Clustering of immunoreceptor tyrosine-based activation motif-containing signalling subunits in CD4+ T cells is an optimal signal for IFN-{gamma} production, but not for the production of IL-4 Int. Immunol., May 1, 2003; 15(5): 665 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. E. Lee, Y. Hori, and A. K. Chakraborty Low T cell receptor expression and thermal fluctuations contribute to formation of dynamic multifocal synapses in thymocytes PNAS, April 15, 2003; 100(8): 4383 - 4388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. R. Carrasco, M. N. Navarro, and M. L. Toribio A Role for the Cytoplasmic Tail of the Pre-T Cell Receptor (TCR) alpha Chain in Promoting Constitutive Internalization and Degradation of the Pre-TCR J. Biol. Chem., April 11, 2003; 278(16): 14507 - 14513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Badran, S. M. Wolinsky, A. Burny, and K. E. Willard-Gallo Identification of Three NFAT Binding Motifs in the 5'-Upstream Region of the Human CD3gamma Gene That Differentially Bind NFATc1, NFATc2, and NF-kappa B p50 J. Biol. Chem., November 27, 2002; 277(49): 47136 - 47148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. Overtvelt, M. Andrieu, V. Verhasselt, F. Connan, J. Choppin, V. Vercruysse, M. Goldman, A. Hosmalin, and B. Vray Trypanosoma cruzi down-regulates lipopolysaccharide-induced MHC class I on human dendritic cells and impairs antigen presentation to specific CD8+ T lymphocytes Int. Immunol., October 1, 2002; 14(10): 1135 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. Schrum and L. A. Turka The Proliferative Capacity of Individual Naive CD4+T Cells Is Amplified by Prolonged T Cell Antigen Receptor Triggering J. Exp. Med., September 16, 2002; 196(6): 793 - 803. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Dumont, N. Blanchard, V. Di Bartolo, N. Lezot, E. Dufour, S. Jauliac, and C. Hivroz TCR/CD3 Down-Modulation and {zeta} Degradation Are Regulated by ZAP-70 J. Immunol., August 15, 2002; 169(4): 1705 - 1712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Borovsky, G. Mishan-Eisenberg, E. Yaniv, and J. Rachmilewitz Serial Triggering of T Cell Receptors Results in Incremental Accumulation of Signaling Intermediates J. Biol. Chem., June 7, 2002; 277(24): 21529 - 21536. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Ise, M. Totsuka, Y. Sogawa, A. Ametani, S. Hachimura, T. Sato, Y. Kumagai, S. Habu, and S. Kaminogawa Naive CD4+ T Cells Exhibit Distinct Expression Patterns of Cytokines and Cell Surface Molecules on Their Primary Responses to Varying Doses of Antigen J. Immunol., April 1, 2002; 168(7): 3242 - 3250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-H. Lee, A. D. Holdorf, M. L. Dustin, A. C. Chan, P. M. Allen, and A. S. Shaw T Cell Receptor Signaling Precedes Immunological Synapse Formation Science, February 22, 2002; 295(5559): 1539 - 1542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Katagiri, M. Hattori, N. Minato, and T. Kinashi Rap1 Functions as a Key Regulator of T-Cell and Antigen-Presenting Cell Interactions and Modulates T-Cell Responses Mol. Cell. Biol., February 15, 2002; 22(4): 1001 - 1015. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Diepolder, N. H. Gruener, J. T. Gerlach, M.-C. Jung, E. A. Wierenga, and G. R. Pape Different Levels of T-Cell Receptor Triggering Induce Distinct Functions in Hepatitis B and Hepatitis C Virus-Specific Human CD4+ T-Cell Clones J. Virol., September 1, 2001; 75(17): 7803 - 7810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Derby, J. Wang, D. H. Margulies, and J. A. Berzofsky Two intermediate-avidity cytotoxic T lymphocyte clones with a disparity between functional avidity and MHC tetramer staining Int. Immunol., June 1, 2001; 13(6): 817 - 824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chan, A. J. T. George, and J. Stark Cooperative enhancement of specificity in a lattice of T cell receptors PNAS, May 8, 2001; 98(10): 5758 - 5763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. T. Belz, W. Xie, and P. C. Doherty Diversity of Epitope and Cytokine Profiles for Primary and Secondary Influenza A Virus-Specific CD8+ T Cell Responses J. Immunol., April 1, 2001; 166(7): 4627 - 4633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. O. Cameron, J. R. Cochran, B. Yassine-Diab, R.-P. Sekaly, and L. J. Stern Cutting Edge: Detection of Antigen-Specific CD4+ T Cells by HLA-DR1 Oligomers Is Dependent on the T Cell Activation State J. Immunol., January 15, 2001; 166(2): 741 - 745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Forestier, F. Deleuil, N. Lapaque, E. Moreno, and J.-P. Gorvel Brucella abortus Lipopolysaccharide in Murine Peritoneal Macrophages Acts as a Down-Regulator of T Cell Activation J. Immunol., November 1, 2000; 165(9): 5202 - 5210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Meyer, C. Trollmo, F. Crawford, P. Marrack, A. C. Steere, B. T. Huber, J. Kappler, and D. A. Hafler Direct enumeration of Borrelia-reactive CD4 T cells ex vivo by using MHC class II tetramers PNAS, September 22, 2000; (2000) 190335897. [Abstract] [Full Text]
|
|
|
|
|
|
A. Qadri, C. G. Radu, J. Thatte, P. Cianga, B. T. Ober, R. J. Ober, and E. S. Ward A Role for the Region Encompassing the c'' Strand of a TCR V{alpha} Domain in T Cell Activation Events J. Immunol., July 15, 2000; 165(2): 820 - 829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. Schrum, A. D. Wells, and L. A. Turka Enhanced surface TCR replenishment mediated by CD28 leads to greater TCR engagement during primary stimulation Int. Immunol., June 1, 2000; 12(6): 833 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. V. Spencer and T. J. Braciale Incomplete Cd8+ T Lymphocyte Differentiation as a Mechanism for Subdominant Cytotoxic T Lymphocyte Responses to a Viral Antigen J. Exp. Med., May 15, 2000; 191(10): 1687 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Lafont, J. Liautard, M. Sable-Teychene, Y. Sainte-Marie, and J. Favero Isopentenyl Pyrophosphate, a Mycobacterial Non-peptidic Antigen, Triggers Delayed and Highly Sustained Signaling in Human gamma delta T Lymphocytes without Inducing Down-modulation of T Cell Antigen Receptor J. Biol. Chem., May 4, 2001; 276(19): 15961 - 15967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Cochran, T. O. Cameron, J. D. Stone, J. B. Lubetsky, and L. J. Stern Receptor Proximity, Not Intermolecular Orientation, Is Critical for Triggering T-cell Activation J. Biol. Chem., July 20, 2001; 276(30): 28068 - 28074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Meyer, C. Trollmo, F. Crawford, P. Marrack, A. C. Steere, B. T. Huber, J. Kappler, and D. A. Hafler Direct enumeration of Borrelia-reactive CD4 T cells ex vivo by using MHC class II tetramers PNAS, October 10, 2000; 97(21): 11433 - 11438. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
