© The Rockefeller University Press, 0022-1007/1998/11/1867/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 10, November 16, 1998 1867-1874
Preselection Thymocytes Are More Sensitive to T Cell Receptor Stimulation Than Mature T Cells
Gayle M. Davey,
Sonya L. Schober,
Bart T. Endrizzi,
Angela K. Dutcher,
Stephen C. Jameson, and
Kristin A. Hogquist
From the Department of Laboratory Medicine and Pathology and Center for Immunology, University of Minnesota, Minneapolis, Minnesota 55455
During T cell development, thymocytes which are tolerant to self-peptides but reactive to foreign peptides are selected. The current model for thymocyte selection proposes that self-peptide–major histocompatibility complex (MHC) complexes that bind the T cell receptor with low affinity will promote positive selection while those with high affinity will result in negative selection. Upon thymocyte maturation, such low affinity self-peptide–MHC ligands no longer provoke a response, but foreign peptides can incidentally be high affinity ligands and can therefore stimulate T cells. For this model to work, thymocytes must be more sensitive to ligand than mature T cells. Contrary to this expectation, several groups have shown that thymocytes are less responsive than mature T cells to anti-T cell receptor for antigen (TCR)/CD3 mAb stimulation. Additionally, the lower TCR levels on thymocytes, compared with T cells, would potentially correlate with decreased thymocyte sensitivity. Here we compared preselection thymocytes and mature T cells for early activation events in response to peptide–MHC ligands. Remarkably, the preselection thymocytes were more responsive than mature T cells when stimulated with low affinity peptide variants, while both populations responded equally well to the antigenic peptide. This directly demonstrates the increased sensitivity of thymocytes compared with T cells for TCR engagement by peptide–MHC complexes.
Key Words: T cell receptor thymus lymphocyte development calcium signaling
Address correspondence to Kristin A. Hogquist or Stephen C. Jameson, Box 334 FUMC, 420 Delaware St. SE, Minneapolis, MN 55455. Phone: 612-626-2403; Fax: 612-625-2199; E-mail: hogqu001{at}tc.umn.edu or james024{at}tc.umn.edu
Abbreviations used: DP, double positive; MESF, molecules of equivalent soluble fluorescence; PEC, peritoneal exudate cells; SP, single positive; Tg, transgenic.

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-
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-
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-
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[Abstract]
[Full Text]
-
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-
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[Abstract]
[Full Text]
-
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[Abstract]
[Full Text]
-
Raman, V., Blaeser, F., Ho, N., Engle, D. L., Williams, C. B., Chatila, T. A.
(2001). Requirement for Ca2+/Calmodulin-Dependent Kinase Type IV/Gr in Setting the Thymocyte Selection Threshold. J. Immunol.
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[Abstract]
[Full Text]
-
Smith, K., Seddon, B., Purbhoo, M. A., Zamoyska, R., Fisher, A. G., Merkenschlager, M.
(2001). Sensory Adaptation in Naive Peripheral CD4 T Cells. JEM
194: 1253-1262
[Abstract]
[Full Text]
-
Wong, P., Barton, G. M., Forbush, K. A., Rudensky, A. Y.
(2001). Dynamic Tuning of T Cell Reactivity by Self-Peptide-Major Histocompatibility Complex Ligands. JEM
193: 1179-1188
[Abstract]
[Full Text]
-
Capone, M., Romagnoli, P., Beermann, F., MacDonald, H. R., van Meerwijk, J. P. M.
(2001). Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells. Blood
97: 1336-1342
[Abstract]
[Full Text]
-
Berg, R. E., Irion, S., Kattman, S., Princiotta, M. F., Staerz, U. D.
(2000). A Physiological Ligand of Positive Selection Is Recognized as a Weak Agonist. J. Immunol.
165: 4209-4216
[Abstract]
[Full Text]
-
Yasutomo, K., Lucas, B., Germain, R. N.
(2000). TCR Signaling for Initiation and Completion of Thymocyte Positive Selection Has Distinct Requirements for Ligand Quality and Presenting Cell Type. J. Immunol.
165: 3015-3022
[Abstract]
[Full Text]
-
Lucas, B., Germain, R. N.
(2000). Opening a Window on Thymic Positive Selection: Developmental Changes in the Influence of Cosignaling by Integrins and CD28 on Selection Events Induced by TCR Engagement. J. Immunol.
165: 1889-1895
[Abstract]
[Full Text]
-
Kersh, G. J., Engle, D. L., Williams, C. B., Allen, P. M.
(2000). Ligand-Specific Selection of MHC Class II-Restricted Thymocytes in Fetal Thymic Organ Culture. J. Immunol.
164: 5675-5682
[Abstract]
[Full Text]
-
Stefanski, H. E., Jameson, S. C., Hogquist, K. A.
(2000). Positive Selection Is Limited by Available Peptide-Dependent MHC Conformations. J. Immunol.
164: 3519-3526
[Abstract]
[Full Text]
-
Fahlen, L., Oberg, L., Brannstrom, T., Khoo, N. K. S., Lendahl, U., Sentman, C. L.
(2000). Ly49A expression on T cells alters T cell selection. Int Immunol
12: 215-222
[Abstract]
[Full Text]
-
Pauza, M., Smith, K. M., Neal, H., Reilly, C., Lanier, L. L., Lo, D.
(2000). Transgenic Expression of Ly-49A in Thymocytes Alters Repertoire Selection. J. Immunol.
164: 884-892
[Abstract]
[Full Text]
-
Pena-Rossi, C., Zuckerman, L. A., Strong, J., Kwan, J., Ferris, W., Chan, S., Tarakhovsky, A., Beyers, A. D., Killeen, N.
(1999). Negative Regulation of CD4 Lineage Development and Responses by CD5. J. Immunol.
163: 6494-6501
[Abstract]
[Full Text]
-
McGargill, M. A., Hogquist, K. A.
(1999). Antigen-Induced Coreceptor Down-Regulation on Thymocytes Is Not a Result of Apoptosis. J. Immunol.
162: 1237-1245
[Abstract]
[Full Text]
-
McNeil, L. K., Evavold, B. D.
(2002). Dissociation of peripheral T cell responses from thymocyte negative selection by weak agonists supports a spare receptor model of T cell activation. Proc. Natl. Acad. Sci. USA
99: 4520-4525
[Abstract]
[Full Text]