Expression and function of the CD3-antigen receptor on murine CD4+8+ thymocytes

Havran, Wendy L.; Poenie, Martin; Kimura, John; Tsien, Roger Y.; Weiss, Arthur; Allison, James P.

doi:10.1038/330170a0

Cited by 236 publications

(122 citation statements)

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“…This is because it would make sense to have a lower threshold for deletion of autoreactive clones, thereby providing a safety margin against autostimulation of mature T cells (42). Several studies have demonstrated that thymocytes are indeed more sensitive to stimulation than mature T cells are (42)(43)(44), but in some assays thymocytes are found to be less responsive (45,46). What we have observed is that the relative sensitivity of thymocytes to stimulation depends on the strength of the ligand considered.…”

Section: Kinetic Proofreading In Negative Selectionsupporting

confidence: 55%

Ligand-Specific Selection of MHC Class II-Restricted Thymocytes in Fetal Thymic Organ Culture

Kersh

Engle

Williams

et al. 2000

The Journal of Immunology

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Positive and negative selection of thymocytes is determined by the specificity of the TCR and signaling through its associated molecules. We have studied selection of thymocytes bearing a MHC class II-restricted TCR using fetal thymic organ culture. This system allows the addition of peptides to the already diverse panoply of endogenous peptide ligands and is useful for analyzing ligand-specific negative selection of CD4 single positive (CD4SP) thymocytes. The data reveal that the ability of a given ligand to mediate negative selection is related to its dissociation rate from the TCR. We find that negative selection is very sensitive, and only the weakest ligand that we can identify fails to induce negative selection. None of the numerous peptides tested were able to induce an increase in CD4SP thymocytes. In addition, the ligands that induce negative selection of CD4SP thymocytes also cause an increase in numbers of CD8SP thymocytes bearing high levels of the class II-restricted TCR. Although these cells have a cell surface phenotype consistent with positive selection, they most likely represent cells in the process of negative selection. Further analysis reveals that these cells are not induced by these ligands in intact adult animals and that their induction is probably only revealed in the organ culture system.

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Section: Kinetic Proofreading In Negative Selectionsupporting

confidence: 55%

Ligand-Specific Selection of MHC Class II-Restricted Thymocytes in Fetal Thymic Organ Culture

Kersh

Engle

Williams

et al. 2000

The Journal of Immunology

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“…Prolonged elevation of [Ca 2ϩ ] i levels and CN activation in T cells are dependent on the capacitative calcium entry, a process that couples the release of calcium from intracellular stores with the influx of extracellular Ca 2ϩ through specialized calcium channels (45,46). Upon stimulation through the TCR/CD3 complex, immature thymocytes show a much lower increase in [Ca 2ϩ ] i compared with mature T cells (47,48). However, co-stimulation through some of the accessory molecules has been shown to enhance and/or prolong the TCR/CD3-mediated increase in [Ca 2ϩ ] i in immature thymocytes (10,49,50) and to potentiate the calcineurin-dependent anti-apoptotic effect (10).…”

Section: Discussionmentioning

confidence: 99%

Successive Expression and Activation of NFAT Family Members during Thymocyte Differentiation

Adachi¹,

Amasaki²,

Miyatake³

et al. 2000

Journal of Biological Chemistry

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Differentiation of immature CD4؉ CD8 ؉ thymocytes to mature CD4 ؉ or CD8 ؉ T cells is induced by positive selection and appears to involve calcineurin-dependent activation of NFAT, a family of transcription factors. NFATx is predominantly expressed in CD4 ؉ CD8 ؉ thymocytes, whereas NFATp and NFATc are expressed at much lower levels in the thymus than in mature T cells. However, how or when each NFAT member is involved in the differentiation pathway is unclear. Using an in vitro model system where isolated CD4 ؉ CD8؉ thymocytes can survive and differentiate into semi-mature CD4-lineage T cells, we suggest that low calcineurin activity sustained for approximately 20 h is required for cell survival and differentiation. Accordingly, the DNA binding activity of NFAT slowly increased during the stimulation of 20 h to induce the differentiation. NFATx significantly contributed to the early rise, but the late increase was mostly due to NFATc activation. Meanwhile, the expression of NFATx mRNA decreased and that of NFATc mRNA increased. The DNA-binding activity of NFATp was detectable but low throughout the stimulation. NFATp became dominantly active after the semi-mature T cells differentiated into mature and activated CD4 T cells. These findings suggest that NFATx and NFATc successively play roles in T cell development.

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“…The most striking finding of the functional studies performed with thymocytes is their lack of correlation with antigen receptor expression (9)(10)(11). We reasoned that a clue to trace the functional fate of early thymocytes may perhaps come from developmental analyses of a third type of cell-surface marker that, unlike TCR-CD3 complex or CD4 and CD8, were selectively expressed on inert thymocytes.…”

Section: )mentioning

confidence: 99%

Delineation of human thymocytes with or without functional potential by CD1-specific antibodies

Hera¹,

Toribio

Martı́nez-A

1989

Int Immunol

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Hematopoletlc precursors lacking T cell antigen receptors (TCR-CD3-) and CD4 and CD8 surface markers (I.e. double-negative thymocytes) give rise to functionally mature T lymphocytes. Yet their major progeny are Immunologlcally unresponsive thymocytes In spite of having acquired TCR -CD3 and CD4 -CD8. Because only mature thymocytes migrate to peripheral lymphold organs and most thymocytes die In situ, the knowledge of the events associated with functional maturation In the double-negative thymocyte progeny Is a fundamental question in T cell development. We reasoned that a clue to trace the fate of early human thymocytes may perhaps come from the study of the developmental acquisition of CD1 antigen, currently used to define better the functionally Inert CD4+8+ (double-positive) stage and absent In mature, medullary thymocytes and peripheral T cells. By using antibodies specific for CD1 (HTA 1/T6) we show here that a large fraction of double-negative thymocytes also express CD1. CD1 +3-, CD1 +3 + , CD1-3+, and CD1-3-subsets all exist. The CD1+3-subset generates CD1+3-4-8+ precursors of CD1 + double-positive cells. A large portion of the CD1 +3+ subset bears TCR75-CD3 complexes. The CD1 -subsets are responsive In assays of function, in which they can be stimulated to use the interleukin 2 pathway of proliferation and to mediate cytotoxiclty. In contrast, all CD1 + thymocytes behave as functionally inert cells. Thus, the CD1 surface marker delineates human thymocyte precursors and their products which lack, or possess, functional potential In vitro, on both a/3 and 76 lineages.

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Expression and function of the CD3-antigen receptor on murine CD4+8+ thymocytes

Cited by 236 publications

References 0 publications

Ligand-Specific Selection of MHC Class II-Restricted Thymocytes in Fetal Thymic Organ Culture

Ligand-Specific Selection of MHC Class II-Restricted Thymocytes in Fetal Thymic Organ Culture

Successive Expression and Activation of NFAT Family Members during Thymocyte Differentiation

Delineation of human thymocytes with or without functional potential by CD1-specific antibodies

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