Modélisation des Réarrangements Vα-Jα du TRA/TRD chez la souris et chez l'homme

V(D)J recombination constitutes a somatic site specific DNA recombination, which originates lymphocyte antigen receptor diversity in jawed vertebrates. Concerning the T cell receptor α chains, V and J genes are used from inside the TRA locus toward distal genes during the successive rearrangements, with no allelic exclusion at the genomic level. Experimental quantifications of particular V-J associations were performed in mouse, giving the tendencies of thymic and peripheral combinatorial repertoires. A stochastic numerical model, based on successive opening windows progressing over the V and J regions during the rearrangement rounds, revealed new insights in the understanding of the dynamical rules governing V-J rearrangements and provided a simulated combinatorial repertoire with the entire V-J association frequencies. In the transition to human, thymic quantifications of certain V-J associations were performed, providing a first experimental wide-ranging sampling of the human TRA combinatorial repertoire. The modeling modeling step offered a clear understanding of the dynamical building of the human α repertoire and proposed predictions on repertoire combinatorial diversity richness. Finally, the precise progression of gene accessibility to rearrangements, according to non-constant opening speeds, together with a synchronized opening of the J regions between both alleles, were sufficient to fully explain both the experimental V-J frequencies currently available for the two species as well as the interallelic J usage.La recombinaison V(D)J constitue une recombinaison somatique et site-spécifique de l'ADN à l'origine de la diversité des récepteurs antigéniques des lymphocytes T chez les vertébrés mandibulés. Concernant la chaîne α des récepteurs T, les gènes V et J sont utilisés depuis l'intérieur du locus TRA vers les gènes distaux durant des réarrangements successifs et ce sans exclusion allélique. La quantification expérimentale de certaines associations V-J chez la souris a permis de définir les tendances des répertoires combinatoires thymiques et périphériques. Un modèle numérique stochastique, basé sur des fenêtrages d'ouverture successives progressant sur les régions V et J durant les cycles de réarrangements, a permis une meilleure compréhension des règles dynamiques gouvernant les réarrangements V-J et a apporté la connaissance d'un répertoire combinatoire simulé renseignant les fréquences de toutes les associations V-J. Lors de la transition à l'homme, la quantification des associations V-J a été réalisée au niveau du thymus, constituant un premier échantillonnage à large échelle du répertoire combinatoire TRA humain. L'étape de modélisation a offert une compréhension claire de la construction dynamique du répertoire α humain et a permis de proposer des prédictions sur la diversité du répertoire combinatoire. Finalement, la progression de l'accessibilité des gènes aux réarrangements selon des vitesses d'ouverture non-constantes associée à une ouverture synchronisée des régions J entre les deux allèles se sont révélées suffisantes pour expliquer les fréquences V-J expérimentales présentement disponibles pour les deux espèces ainsi que l'utilisation interallélique des gènes J

Quantitative and Qualitative Changes in V-J α Rearrangements During Mouse Thymocytes Differentiation: Implication For a Limited T Cell Receptor α Chain Repertoire

Knowledge of the complete nucleotide sequence of the mouse TCRAD locus allows an accurate determination V-J rearrangement status. Using multiplex genomic PCR assays and real time PCR analysis, we report a comprehensive and systematic analysis of the V-J recombination of TCR α chain in normal mouse thymocytes during development. These respective qualitative and quantitative approaches give rise to four major points describing the control of gene rearrangements. (a) The V-J recombination pattern is not random during ontogeny and generates a limited TCR α repertoire; (b) V-J rearrangement control is intrinsic to the thymus; (c) each V gene rearranges to a set of contiguous J segments with a gaussian-like frequency; (d) there are more rearrangements involving V genes at the 3′ side than 5′ end of V region. Taken together, this reflects a preferential association of V and J gene segments according to their respective positions in the locus, indicating that accessibility of both V and J regions is coordinately regulated, but in different ways. These results provide a new insight into TCR α repertoire size and suggest a scenario for V usage during differentiation

Numerical Modelling Of The V-J Combinations Of The T Cell Receptor TRA/TRD Locus

T-Cell antigen Receptor (TR) repertoire is generated through rearrangements of V and J genes encoding α and β chains. The quantification and frequency for every V-J combination during ontogeny and development of the immune system remain to be precisely established. We have addressed this issue by building a model able to account for Vα-Jα gene rearrangements during thymus development of mice. So we developed a numerical model on the whole TRA/TRD locus, based on experimental data, to estimate how Vα and Jα genes become accessible to rearrangements. The progressive opening of the locus to V-J gene recombinations is modeled through windows of accessibility of different sizes and with different speeds of progression. Furthermore, the possibility of successive secondary V-J rearrangements was included in the modelling. The model points out some unbalanced V-J associations resulting from a preferential access to gene rearrangements and from a non-uniform partition of the accessibility of the J genes, depending on their location in the locus. The model shows that 3 to 4 successive rearrangements are sufficient to explain the use of all the V and J genes of the locus. Finally, the model provides information on both the kinetics of rearrangements and frequencies of each V-J associations. The model accounts for the essential features of the observed rearrangements on the TRA/TRD locus and may provide a reference for the repertoire of the V-J combinatorial diversity

"Immunetworks", intersecting circuits and dynamics

International audienceThis paper proposes a study of biological regulation networks based on a multi-level strategy. Given a network, the first structural level of this strategy consists in analysing the architecture of the network interactions in order to describe it. The second dynamical level consists in relating the patterns found in the architecture to the possible dynamical behaviours of the network. It is known that circuits are the patterns that play the most important part in the dynamics of a network in the sense that they are responsible for the diversity of its asymptotic behaviours. Here, we pursue further this idea and argue that beyond the influence of underlying circuits, intersections of circuits also impact significantly on the dynamics of a network and thus need to be payed special attention to. For some genetic regulation networks involved in the control of the immune system ("immunetworks"), we show that the small number of attractors can be explained by the presence, in the underlying structures of these networks, of intersecting circuits that "inter-lock"

Estimation of Daily Reproduction Numbers during the COVID-19 Outbreak

(1) Background: The estimation of daily reproduction numbers throughout the contagiousness period is rarely considered, and only their sum R0 is calculated to quantify the contagiousness level of an infectious disease. (2) Methods: We provide the equation of the discrete dynamics of the epidemic’s growth and obtain an estimation of the daily reproduction numbers by using a deconvolution technique on a series of new COVID-19 cases. (3) Results: We provide both simulation results and estimations for several countries and waves of the COVID-19 outbreak. (4) Discussion: We discuss the role of noise on the stability of the epidemic’s dynamics. (5) Conclusions: We consider the possibility of improving the estimation of the distribution of daily reproduction numbers during the contagiousness period by taking into account the heterogeneity due to several host age classes

Numerical Modelling Of The V-J Combinations Of The T Cell Receptor TRA/TRD Locus

International audienceLymphocytes of the immune system ensure the body defense by the expression of receptors which are specific of targets, termed antigens. Each lymphocyte, deriving from the same original clone, expresses the same unique receptor. To achieve the production of receptors covering the wide variety of antigens, lymphocytes use a specialized genetic mechanism consisting of gene rearrangements. For instance, the genes encoding the receptor of the alpha chain of the T lymphocyte receptor (TRA) spread over a 1500 Kb genetic region which includes around 100 V genes, 60 J genes, and a single C gene. To constitute a functional alpha chain, one of the V and one of the J genes rearrange together to form a single exon. The precise definition of these V-J combinations is essential to understand the repertoire of TRA. We have developed a numerical model simulating all of the V-J combinations of TRA, fitting the available experimental observations obtained from the analysis of TRA in T lymphocytes of the thymus and the blood. Our model gives new insights on the rules controlling the use of V and J genes in providing a dynamic estimation of the total V-J combinations

IMGT/GeneInfo: enhancing V(D)J recombination database accessibility

IMGT/GeneInfo is a user-friendly online information system that provides information on data resulting from the complex mechanisms of immunoglobulin (IG) and T cell receptor (TR) V(D)J recombinations. For the first time, it is possible to visualize all the rearrangement parameters on a single page. IMGT/GeneInfo is part of the international ImMunoGeneTics information system® (IMGT), a high-quality integrated knowledge resource specializing in IG, TR, major histocompatibility complex (MHC), and related proteins of the immune system of human and other vertebrate species. The IMGT/GeneInfo system was developed by the TIMC and ICH laboratories (with the collaboration of LIGM), and is the first example of an external system being incorporated into IMGT. In this paper, we report the first part of this work. IMGT/GeneInfo_TR deals with the human and mouse TRA/TRD and TRB loci of the TR. Data handling and visualization are complementary to the current data and tools in IMGT, and will subsequently allow the modelling of V(D)J gene use, and thus, to predict non-standard recombination profiles which may eventually be found in conditions such as leukaemias or lymphomas. Access to IMGT/GeneInfo is free and can be found at http://imgt.cines.fr/GeneInfo