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Deriving quantitative constraints on T cell selection from data on the mature T cell repertoire
V Detours1, R Mehr, A S Perelson
1Theoretical Biology and Biophysics, Center for Nonlinear Studies, Los Alamos National Laboratory, NM 87545, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|December 22, 1999
Summary
T cell selection in the thymus is affinity-driven. This process requires T cell receptors (TCRs) to recognize more peptide than MHC residues, extensive negative selection, and specific numbers of thymic cell divisions.
Area of Science:
- Immunology
- T cell biology
- Thymic selection
Background:
- The T cell repertoire is established in the thymus via positive and negative selection processes.
- Understanding these selection mechanisms is crucial for deciphering T cell receptor (TCR) generation and function.
- The mature T cell repertoire provides insights into the operation of thymic selection.
Purpose of the Study:
- To derive quantitative constraints for affinity-driven T cell selection.
- To reconcile experimental observations of alloreactivity, self-MHC restriction, and foreign antigen recognition frequencies with selection models.
- To investigate the parameters governing TCR generation and selection in the thymus.
Main Methods:
- Modeling T cell selection based on the assumption of affinity-driven processes.
- Deriving quantitative constraints on selection parameters.
- Comparing model predictions with experimentally observed immunological data.
Main Results:
- Affinity-driven selection is consistent with experimental data under specific conditions.
- TCRs must recognize more peptide residues than MHC polymorphic residues.
- The majority of positively selected T cell clones undergo deletion via negative selection.
- Between 1 and 3.6 T cell divisions occur post-TCR rearrangement in the thymus.
- Selection is driven by a large repertoire of self-peptides (10^3-10^5).
Conclusions:
- The study provides quantitative support for an affinity-driven model of T cell selection.
- Specific molecular and cellular parameters are necessary for thymic selection to generate a functional T cell repertoire.
- These findings offer a framework for understanding T cell development and its implications for immune responses.