A quantitative theory of affinity-driven T cell repertoire selection

Area of Science:

• Immunology
• Computational Biology
• Theoretical Biology

Background:

• T cell receptor (TCR) binding to peptide-MHC complexes is crucial for T cell development and activation.
• Thymic selection, comprising positive and negative selection, shapes the T cell repertoire.
• The mature T cell repertoire exhibits self-MHC restriction and significant alloreactivity.

Purpose of the Study:

• To derive mathematical expressions for alloreactivity, self-MHC restriction, and foreign peptide activation frequency.
• To analyze the influence of various parameters on T cell repertoire generation and selection.
• To investigate the role of MHC and peptide contributions to TCR binding in shaping the repertoire.

Main Methods:

• Development of a mathematical model using a simplified digit string representation for T cell receptors.
• Derivation of formulas relating repertoire characteristics to selection stringencies and binding parameters.
• Analysis of the relative contributions of MHC and peptide residues to TCR binding.

Main Results:

• Mathematical expressions were derived for alloreactivity, self-MHC restriction, and foreign peptide activation.
• The relative, not absolute, contribution of MHC and peptide to TCR binding is critical for repertoire shaping.
• Alloreactivity levels can be inferred from selection stringency and are unaffected by thymic selection.

Conclusions:

• The study provides a quantitative framework for understanding T cell repertoire formation.
• Relative binding contributions of MHC and peptides are key determinants of T cell repertoire characteristics.
• Alloreactivity is directly linked to selection stringency, independent of thymic selection processes.