NOD genetic variation influences ab/gd lineage decisions when TCRa is prematurely expressed, but not the process of negative selection.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE34936 | GEO | 2012/01/10
SECONDARY ACCESSION(S): PRJNA150987
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the following subset Series: GSE34934: Expression data from BDC2.5 TCR Tg, preselected Rag-/-.B6 and Rag-/-.NOD.H2b thymocytes upon antigenic stimulation GSE34935: Expression data from BDC2.5 TCR Tg thymocytes on B6g7 and NOD background Refer to individual Series
2012-01-10 | E-GEOD-34936 | biostudies-arrayexpress
Project description:The ability to rapidly and flexibly adapt decisions to available rewards is crucial for survival in dynamic environments. Reward-based decisions are guided by reward expectations that are updated based on prediction errors, and processing of these errors involves dopaminergic neuromodulation in the striatum. To test the hypothesis that the COMT gene Val(158)Met polymorphism leads to interindividual differences in reward-based learning, we used the neuromodulatory role of dopamine in signaling prediction errors. We show a behavioral advantage for the phylogenetically ancestral Val/Val genotype in an instrumental reversal learning task that requires rapid and flexible adaptation of decisions to changing reward contingencies in a dynamic environment. Implementing a reinforcement learning model with a dynamic learning rate to estimate prediction error and learning rate for each trial, we discovered that a higher and more flexible learning rate underlies the advantage of the Val/Val genotype. Model-based fMRI analysis revealed that greater and more differentiated striatal fMRI responses to prediction errors reflect this advantage on the neurobiological level. Learning rate-dependent changes in effective connectivity between the striatum and prefrontal cortex were greater in the Val/Val than Met/Met genotype, suggesting that the advantage results from a downstream effect of the prefrontal cortex that is presumably mediated by differences in dopamine metabolism. These results show a critical role of dopamine in processing the weight a particular prediction error has on the expectation updating for the next decision, thereby providing important insights into neurobiological mechanisms underlying the ability to rapidly and flexibly adapt decisions to changing reward contingencies.
| S-EPMC2760487 | biostudies-literature
Project description:Comparison of gd T cell clones with ab T cell clones that responded to the same antigen. Clones were identically stimulated with ConA/IL-2 and analyzed with two separate microarrays. Keywords: other
2005-08-23 | GSE2704 | GEO
Project description:Signaling via the pre-T cell antigen receptor (pre-TCR) and the receptor Notch1 induces transient self-renewal (β-selection) of TCRβ(+) CD4(-)CD8(-) double-negative stage 3 (DN3) and DN4 progenitor cells that differentiate into CD4(+)CD8(+) double-positive (DP) thymocytes, which then rearrange the locus encoding the TCR α-chain (Tcra). Interleukin 7 (IL-7) promotes the survival of TCRβ(-) DN thymocytes by inducing expression of the pro-survival molecule Bcl-2, but the functions of IL-7 during β-selection have remained unclear. Here we found that IL-7 signaled TCRβ(+) DN3 and DN4 thymocytes to upregulate genes encoding molecules involved in cell growth and repressed the gene encoding the transcriptional repressor Bcl-6. Accordingly, IL-7-deficient DN4 cells lacked trophic receptors and did not proliferate but rearranged Tcra prematurely and differentiated rapidly. Deletion of Bcl6 partially restored the self-renewal of DN4 cells in the absence of IL-7, but overexpression of BCL2 did not. Thus, IL-7 critically acts cooperatively with signaling via the pre-TCR and Notch1 to coordinate proliferation, differentiation and Tcra recombination during β-selection.
| S-EPMC4368453 | biostudies-literature
Project description:Comparison of gd T cell clones with ab T cell clones that responded to the same antigen. Clones were identically stimulated with ConA/IL-2 and analyzed with two separate microarrays. Keywords: other
2010-06-09 | E-GEOD-2704 | biostudies-arrayexpress
Project description:Perceptual decision making has been widely studied using tasks in which subjects are asked to discriminate a visual stimulus and instructed to report their decision with a movement. In these studies, performance is measured by assessing the accuracy of the participants' choices as a function of the ambiguity of the visual stimulus. Typically, the reporting movement is considered as a mere means of reporting the decision with no influence on the decision-making process. However, recent studies have shown that even subtle differences of biomechanical costs between movements may influence how we select between them. Here we investigated whether this purely motor cost could also influence decisions in a perceptual discrimination task in detriment of accuracy. In other words, are perceptual decisions only dependent on the visual stimulus and entirely orthogonal to motor costs? Here we show the results of a psychophysical experiment in which human subjects were presented with a random dot motion discrimination task and asked to report the perceived motion direction using movements of different biomechanical cost. We found that the pattern of decisions exhibited a significant bias towards the movement of lower cost, even when this bias reduced performance accuracy. This strongly suggests that motor costs influence decision making in visual discrimination tasks for which its contribution is neither instructed nor beneficial.
| S-EPMC4684499 | biostudies-literature
Project description:Based on analyses of multiple TCR transgenic (tg) models, the emergence of pathogenic T cells in diabetes-prone NOD mice has been ascribed to a failure to censure autoreactive clones in the thymus. In contrast, using isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic variation impairs neither clonal deletion nor downstream transcriptional programs. However, we find that NOD genetic variation influences ??/??-lineage decisions promoted by early expression of tg ??-TCRs at the double-negative (DN) stage. In B6 and other genetic backgrounds, tg ??-TCRs behave like ??-TCRs and commit a large fraction of DNs toward the ??-lineage, thereby decreasing the size of the double-positive (DP) pool, which is efficiently positively and negatively selected. In NOD DNs, ??-TCR signalosomes instead behave like pre-TCRs, resulting in high numbers of DPs competing for limited selection niches, and poor positive and negative selection. Once niche effects are neutralized in mixed bone marrow chimeras, positive and negative selection are equally efficient on B6 and NOD backgrounds. Biochemical analysis revealed a selective defect in the activation of Erk1/2 downstream of NOD ??-TCR signalosomes. Therefore, NOD genetic variation influences ??/??-lineage decisions when the ??-TCR heterodimer is prematurely expressed, but not the process of negative selection.
| S-EPMC3302233 | biostudies-literature
Project description:Adaptive immunity depends on diverse T cell receptor repertoires generated by variable, diversity, and joining (V[D]J) recombination. Here, we define the principles by which combinatorial diversity is generated in the murine Tcra repertoire. Tcra and Tcrd gene segments share the Tcra-Tcrd locus, with interspersed Vα and Vδ segments undergoing Vδ-Dδ-Jδ rearrangement in CD4-CD8- thymocytes and then multiple rounds of Vα-Jα rearrangement in CD4+CD8+ thymocytes. We document stepwise, highly coordinated proximal-to-distal progressions of Vα and Jα use on individual Tcra alleles, limiting combinatorial diversity. This behavior is supported by an extended chromatin conformation in CD4+CD8+ thymocytes, with only nearby Vα and Jα segments contacting each other. Tcrd rearrangements can use distal Vδ segments due to a contracted Tcra-Tcrd conformation in CD4-CD8- thymocytes. These rearrangements expand the Tcra repertoire by truncating the Vα array to permit otherwise disfavored Vα-Jα combinations. Therefore, recombination events at two developmental stages with distinct chromatin conformations synergize to promote Tcra repertoire diversity.
| S-EPMC5529038 | biostudies-literature
Project description:Efficient cognitive decisions should be adjustable to incoming novel information. However, most current models of decision making have so far neglected any potential interaction between intentional and stimulus-driven decisions. We report here behavioral results and a new model on the interaction between a perceptual decision and non-predictable novel information. We asked participants to anticipate their response to an external stimulus and presented this stimulus with variable delay. Participants were clearly able to adjust their initial decision to the new stimulus if this latter appeared sufficiently early. To account for these results, we present a two-stage model in which two systems, an intentional and a stimulus-driven, interact only in the second stage. In the first stage of the model, the intentional and stimulus-driven processes race independently to reach a transition threshold between the two stages. The model can also account for results of a second experiment where a response bias is introduced. Our model is consistent with some physiological results that indicate that both parallel and interactive processing take place between intentional and stimulus-driven information. It emphasizes that in natural conditions, both types of processing are important and it helps pinpoint the transition between parallel and interactive processing.
| S-EPMC3617197 | biostudies-literature
Project description:Antigen receptor locus V(D)J recombination requires interactions between widely separated variable (V), diversity (D), and joining (J) gene segments, but the mechanisms that generate these interactions are not well understood. Here we assessed mechanisms that direct developmental stage-specific long-distance interactions at the Tcra/Tcrd locus. The Tcra/Tcrd locus recombines Tcrd gene segments in CD4(-)CD8(-) double-negative thymocytes and Tcra gene segments in CD4(+)CD8(+) double-positive thymocytes. Initial V(α)-to-J(α) recombination occurs within a chromosomal domain that displays a contracted conformation in both thymocyte subsets. We used chromosome conformation capture to demonstrate that the Tcra enhancer (E(α)) interacts directly with V(α) and J(α) gene segments distributed across this domain, specifically in double-positive thymocytes. Moreover, E(α) promotes interactions between these V(α) and J(α) segments that should facilitate their synapsis. We found that the CCCTC-binding factor (CTCF) binds to E(α) and to many locus promoters, biases E(α) to interact with these promoters, and is required for efficient V(α)-J(α) recombination. Our data indicate that E(α) and CTCF cooperate to create a developmentally regulated chromatin hub that supports V(α)-J(α) synapsis and recombination.
| S-EPMC3528579 | biostudies-literature