TCRβ Allelic Exclusion in Dynamical Models of V(D)J Recombination Based on Allele Independence

• Published in: The Journal of immunology (1950) Vol. 185; no. 3; pp. 1622 - 1632
• Main Authors: Farcot, Etienne, Bonnet, Marie, Jaeger, Sébastien, Spicuglia, Salvatore, Fernandez, Bastien, Ferrier, Pierre
• Format: Journal Article
• Language: English
• Published: United States Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists 01.08.2010
• Subjects: Alleles; Animals; Antibody Diversity; Antibody Diversity - genetics; Feedback, Physiological; Gene Rearrangement, T-Lymphocyte; Gene Rearrangement, T-Lymphocyte - immunology; Immunoglobulin Joining Region; Immunoglobulin Joining Region - biosynthesis; Immunoglobulin Joining Region - genetics; Immunoglobulin Variable Region; Immunoglobulin Variable Region - biosynthesis; Immunoglobulin Variable Region - genetics; Immunology; Life Sciences; Markov Chains; Mice; Mice, Knockout; Models, Immunological; Molecular Dynamics Simulation; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, alpha-beta - genetics; Recombination, Genetic; Recombination, Genetic - immunology; T-Lymphocyte Subsets; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets; Recombination; Markov Chains; Antibody Diversity; Genetic; T-Cell; Knockout; Molecular Dynamics Simulation; Antigen; Receptors; alpha-beta; Animals; Feedback; Gene Rearrangement; T-Lymphocyte; Alleles; Mice; Immunoglobulin Variable Region; Models; Immunoglobulin Joining Region; Physiological; Immunological
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.0904182

Allelic exclusion represents a major aspect of TCRβ gene assembly by V(D)J recombination in developing T lymphocytes. Despite recent progress, its comprehension remains problematic when confronted with experimental data. Existing models fall short in terms of incorporating into a unique distribution all the cell subsets emerging from the TCRβ assembly process. To revise this issue, we propose dynamical, continuous-time Markov chain-based modeling whereby essential steps in the biological procedure (D-J and V-DJ rearrangements and feedback inhibition) evolve independently on the two TCRβ alleles in every single cell while displaying random modes of initiation and duration. By selecting parameters via fitting procedures, we demonstrate the capacity of the model to offer accurate fractions of all distinct TCRβ genotypes observed in studies using developing and mature T cells from wild-type or mutant mice. Selected parameters in turn afford relative duration for each given step, hence updating TCRβ recombination distinctive timings. Overall, our dynamical modeling integrating allele independence and noise in recombination and feedback-inhibition events illustrates how the combination of these ingredients alone may enforce allelic exclusion at the TCRβ locus.