TCR beta allelic exclusion in dynamical models of V(D)J recombination based on allele independence.
Allelic exclusion represents a major aspect of TCRbeta 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 TCRbeta 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 TCRbeta 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 TCRbeta 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 TCRbeta 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 TCRbeta locus.
Farcot
Etienne
E
Centre de Physique Théorique, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6207, Université de la Méditerranée-Université de Provence-Université Sud Toulon Var, Centre National de la Recherche Scientifique Luminy Case 907, France.
Bonnet
Marie
M
Jaeger
Sébastien
S
Spicuglia
Salvatore
S
Fernandez
Bastien
B
Ferrier
Pierre
P
D000483:Alleles; D000818:Animals; D000916:Antibody Diversity / Q000235:genetics*; D025461:Feedback, Physiological; D015329:Gene Rearrangement, T-Lymphocyte / Q000276:immunology; D007133:Immunoglobulin Joining Region / Q000096:biosynthesis / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics*; D008390:Markov Chains; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D056004:Molecular Dynamics Simulation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D011995:Recombination, Genetic / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D016693:Receptors, Antigen, T-Cell, alpha-beta