Tuning of Activation Thresholds Explains Flexibility in the Selection and Development of T Cells in the Thymus

Immature CD4+CD8+thymocytes expressing T-cell antigen receptors (TCR) are selected by TCR-mediated recognition of peptides associated with major histocompatibility complex molecules on thymic stromal cells. Selection ensures reactivity of the mature cells to foreign antigens and tolerance to self. A...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1996-12, Vol.93 (25), p.14747-14752
Main Authors: Grossman, Zvi, Singer, Alfred
Format: Article
Language:English
Subjects:
Animals
Antigen presenting cells
Antigens
Biological Sciences
Cell Differentiation
Developmental biology
Humans
Ligands
Models, Biological
Molecules
Negative selection
Receptors
Receptors, Antigen, T-Cell - immunology
T cell antigen receptors
T lymphocytes
T-Lymphocytes - cytology
T-Lymphocytes - immunology
Thymocytes
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Summary:Immature CD4+CD8+thymocytes expressing T-cell antigen receptors (TCR) are selected by TCR-mediated recognition of peptides associated with major histocompatibility complex molecules on thymic stromal cells. Selection ensures reactivity of the mature cells to foreign antigens and tolerance to self. Although much has been learned about the factors that determine whether a thymocyte with a given specificity will be positively or negatively selected, selection as an aspect of the developmental process as a whole is less well-understood. Here we invoke a model in which thymocytes tune their response characteristics individually and dynamically in the course of development. Cellular development and selection are driven by receptor-mediated metabolic perturbations. Perturbation is a measure of the net intracellular change induced by external stimulation. It results from the integration of several signals and countersignals over time and therefore depends on the environment and the maturation stage of the cell. Individual cell adaptation limits the range of perturbations. Such adaptation renders thymocytes less sensitive to the level of stimulation per se, but responsive to environmental changes in that level. This formulation begins to explain the mechanisms that link developmental and selection events to each other.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.93.25.14747