Individual Repertoires Research Articles

Rapid Assessment of T-Cell Receptor Specificity of the Immune Repertoire.

Accurate assessment of TCR-antigen specificity at the whole immune repertoire level lies at the heart of improved cancer immunotherapy, but predictive models capable of high-throughput assessment of TCR-peptide pairs are lacking. Recent advances in deep sequencing and crystallography have enriched the data available for studying TCR-p-MHC systems. Here, we introduce a pairwise energy model, RACER, for rapid assessment of TCR-peptide affinity at the immune repertoire level. RACER applies supervised machine learning to efficiently and accurately resolve strong TCR-peptide binding pairs from weak ones. The trained parameters further enable a physical interpretation of interacting patterns encoded in each specific TCR-p-MHC system. When applied to simulate thymic selection of an MHC-restricted T-cell repertoire, RACER accurately estimates recognition rates for tumor-associated neoantigens and foreign peptides, thus demonstrating its utility in helping address the large computational challenge of reliably identifying the properties of tumor antigen-specific T-cells at the level of an individual patient's immune repertoire.

Age and CMV-Infection Jointly Affect the EBV-Specific CD8+ T-Cell Repertoire.

CD8+ T cells play an important role in protection against viral infections. With age, changes in the T-cell pool occur, leading to diminished responses against both new and recurring infections in older adults. This is thought to be due to a decrease in both T-cell numbers and T-cell receptor (TCR) diversity. Latent infection with cytomegalovirus (CMV) is assumed to contribute to this age-associated decline of the immune system. The observation that the level of TCR diversity in the total memory T-cell pool stays relatively stable during aging is remarkable in light of the constant input of new antigen-specific memory T cells. What happens with the diversity of the individual antigen-specific T-cell repertoires in the memory pool remains largely unknown. Here we studied the effect of aging on the phenotype and repertoire diversity of CMV-specific and Epstein-Barr virus (EBV)-specific CD8+ T cells, as well as the separate effects of aging and CMV-infection on the EBV-specific T-cell repertoire. Antigen-specific T cells against both persistent viruses showed an age-related increase in the expression of markers associated with a more differentiated phenotype, including KLRG-1, an increase in the fraction of terminally differentiated T cells, and a decrease in the diversity of the T-cell repertoire. Not only age, but also CMV infection was associated with a decreased diversity of the EBV-specific T-cell repertoire. This suggests that both CMV infection and age can impact the T-cell repertoire against other antigens.

Типические места Малодербетовского цикла эпоса «Джангар» как средство определения авторства сказителя

Introduction. Russian folklorists have tended — and still do — to focus on formula-type language patterns inherent to traditional epic poetry. The shaping of epic songs would be facilitated by the wide use of structurally identical and stylistically similar descriptions and situations referred to as loci communes (‘typical passages’). Goals. The paper aims at identifying the personality of the taleteller to have recited the Baga Dorbet (Russ. Maloderbetovsky) cycle of the Jangar epic. With this in view, the work reveals typical passages of the Cycle, provides comparative insights into ones within prologues of the Cycle, compares the typical passages to similar elements from other cycles and individual repertoires. Materials and Methods. The study employs the methodology developed by P. D. Ukhov for the classification of Russian bylinas, and analyzes Jangar epic songs from the Baga Dorbet and Baga Tsokhor cycles, repertoires of such renown jangarchis as Eelyan Ovla, Mukӧvün Basangov, Dava Shavaliev, Nasanka Baldyrov, and Badma Obushinov. Conclusions. Typical passages of the Baga Dorbet cycle are structurally identical and stylistically homogenous descriptions where both syntactic patterns and described details and grammatical forms of parts of speech coincide which attests to that the texts were authored by (recorded from) one and the same taleteller. The opinion is confirmed by the below given examples of typical passages from other cycles that differ not only in terms of style or structure, but the very depicted objects, events, participants of the feast, the seating chart of theirs, and even numbers and sequence of stanzas significantly vary. The differences are determined by that the taletellers were representing different epic performance traditions with certain narrative patterns inherited from their predecessors. The comparative analysis of typical passages from the Baga Dorbet cycle shows the taleteller not only reproduces the once learnt song but rather creatively approaches every single performance maintaining standard elements of typical passages, modifies epic formulas employing synonyms, rearranging stanzas, reducing or adding details of descriptions, etc. This can be explained by that ‘above all in epic memory is not the formula precisely and intactly articulated in words but the artistic content, the taleteller (who) adheres to the framework of epic knowledge <...> (to) select one of the possible paths’, since this epic knowledge is wider than the text recited. So, the study concludes the whole of the Baga Dorbet cycle was recorded from (authored by) one taleteller and students whose names still remains unknown.

Intra-individual variation in adults and children: measuring and conceptualizing individual dialect–standard repertoires

AbstractThis paper explores intra-individual variation as a manifestation of language-internal multilingualism in the Central-Bavarian Austrian context. Based on speech data from children and adults in different contexts, we discuss different methods of measuring and analyzing inter-situational variation along the dialect and standard language spectrum. By contrasting measures of dialectality, on the one hand, and proportions of turns in dialect, standard language or intermediate/mixed forms on the other, we gain complementary insights not only into the individual dialect-standard repertoires but also into the consequences of different methodological choices. The results indicate that intra-individual variation is ubiquitous in adults and children and that individual repertoires need to be taken into account from the beginning of the language acquisition process. We suggest that while intra-individual variation can be attested through the use of various methods, the revealed level of granularity and the conclusions that can be drawn as to the individual repertoires on the dialect-standard spectrum largely depend on the measures used and their inherent assumptions and intrinsically necessary categorizations.

Public Baseline and shared response structures support the theory of antibody repertoire functional commonality.

The naïve antibody/B-cell receptor (BCR) repertoires of different individuals ought to exhibit significant functional commonality, given that most pathogens trigger an effective antibody response to immunodominant epitopes. Sequence-based repertoire analysis has so far offered little evidence for this phenomenon. For example, a recent study estimated the number of shared ('public') antibody clonotypes in circulating baseline repertoires to be around 0.02% across ten unrelated individuals. However, to engage the same epitope, antibodies only require a similar binding site structure and the presence of key paratope interactions, which can occur even when their sequences are dissimilar. Here, we search for evidence of geometric similarity/convergence across human antibody repertoires. We first structurally profile naïve ('baseline') antibody diversity using snapshots from 41 unrelated individuals, predicting all modellable distinct structures within each repertoire. This analysis uncovers a high (much greater than random) degree of structural commonality. For instance, around 3% of distinct structures are common to the ten most diverse individual samples ('Public Baseline' structures). Our approach is the first computational method to find levels of BCR commonality commensurate with epitope immunodominance and could therefore be harnessed to find more genetically distant antibodies with same-epitope complementarity. We then apply the same structural profiling approach to repertoire snapshots from three individuals before and after flu vaccination, detecting a convergent structural drift indicative of recognising similar epitopes ('Public Response' structures). We show that Antibody Model Libraries derived from Public Baseline and Public Response structures represent a powerful geometric basis set of low-immunogenicity candidates exploitable for general or target-focused therapeutic antibody screening.

Utilizing Computational Machine Learning Tools to Understand Immunogenic Breadth in the Context of a CD8 T-Cell Mediated HIV Response.

Predictive models are becoming more and more commonplace as tools for candidate antigen discovery to meet the challenges of enabling epitope mapping of cohorts with diverse HLA properties. Here we build on the concept of using two key parameters, diversity metric of the HLA profile of individuals within a population and consideration of sequence diversity in the context of an individual's CD8 T-cell immune repertoire to assess the HIV proteome for defined regions of immunogenicity. Using this approach, analysis of HLA adaptation and functional immunogenicity data enabled the identification of regions within the proteome that offer significant conservation, HLA recognition within a population, low prevalence of HLA adaptation and demonstrated immunogenicity. We believe this unique and novel approach to vaccine design as a supplement to vitro functional assays, offers a bespoke pipeline for expedited and rational CD8 T-cell vaccine design for HIV and potentially other pathogens with the potential for both global and local coverage.

Low Levels of Natural Anti-α-N-Acetylgalactosamine (Tn) Antibodies Are Associated With COVID-19.

Human serum contains large amounts of anti-carbohydrate antibodies, some of which may recognize epitopes on viral glycans. Here, we tested the hypothesis that such antibodies may confer protection against COVID-19 so that patients would be preferentially found among people with low amounts of specific anti-carbohydrate antibodies since individual repertoires vary considerably. After selecting glycan epitopes commonly represented in the human anti-carbohydrate antibody repertoire that may also be expressed on viral glycans, plasma levels of the corresponding antibodies were determined by ELISA in 88 SARS-CoV-2 infected individuals, including 13 asymptomatic, and in 82 non-infected controls. We observed that anti-Tn antibodies levels were significantly lower in patients as compared to non-infected individuals. This was not observed for any of the other tested carbohydrate epitopes, including anti-αGal antibodies used as a negative control since the epitope cannot be synthesized by humans. Owing to structural homologies with blood groups A and B antigens, we also observed that anti-Tn and anti-αGal antibodies levels were lower in blood group A and B, respectively. Analyses of correlations between anti-Tn and the other anti-carbohydrates tested revealed divergent patterns of correlations between patients and controls, suggesting qualitative differences in addition to the quantitative difference. Furthermore, anti-Tn levels correlated with anti-S protein levels in the patients’ group, suggesting that anti-Tn might contribute to the development of the specific antiviral response. Overall, this first analysis allows to hypothesize that natural anti-Tn antibodies might be protective against COVID-19.

Stable leaders pave the way for cooperation under time-dependent exploration rates.

The exploration of different behaviours is part of the adaptation repertoire of individuals to new environments. Here, we explore how the evolution of cooperative behaviour is affected by the interplay between exploration dynamics and social learning, in particular when individuals engage on prisoner’s dilemma along the edges of a social network. We show that when the population undergoes a transition from strong to weak exploration rates a decline in the overall levels of cooperation is observed. However, if the rate of decay is lower in highly connected individuals (Leaders) than for the less connected individuals (Followers) then the population is able to achieve higher levels of cooperation. Finally, we show that minor differences in selection intensities (the degree of determinism in social learning) and individual exploration rates, can translate into major differences in the observed collective dynamics.

Landscape of T-cell repertoires with public COVID-19-associated T-cell receptors in pre-pandemic risk cohorts.

ObjectivesT cells have an essential role in the antiviral defence. Public T‐cell receptor (TCR) clonotypes are expanded in a substantial proportion of COVID‐19 patients. We set out to exploit their potential use as read‐out for COVID‐19 T‐cell immune responses.MethodsWe searched for COVID‐19‐associated T‐cell clones with public TCRs, as defined by identical complementarity‐determining region 3 (CDR3) beta chain amino acid sequence that can be reproducibly detected in the blood of COVID‐19 patients. Of the different clonotype identification algorithms used in this study, deep sequencing of brain tissue of five patients with fatal COVID‐19 delivered 68 TCR clonotypes with superior representation across 140 immune repertoires of unrelated COVID‐19 patients.ResultsMining of immune repertoires from subjects not previously exposed to the virus showed that these clonotypes can be found in almost 20% of pre‐pandemic immune repertoires of healthy subjects, with lower representation in repertoires from risk groups like individuals above the age of 60 years or patients with cancer.ConclusionTogether, our data show that at least a proportion of the SARS‐CoV‐2 T‐cell response is mediated by public TCRs that are present in repertoires of unexposed individuals. The lower representation of these clones in repertoires of risk groups or failure to expand such clones may contribute to more unfavorable clinical COVID‐19 courses.

Megszólítási gyakorlatok és stratégiák az oktató-hallgató viszonyban

The aim of this paper is to show how Hungarian address practices are working in the context of higher education. The study also offers a description of interpretations and ideologies related to these practices. The research is based on questionnaires, individual and focus-group interviews conducted with teachers and students of a university institute training Hungarian teachers. The data reveal that the reciprocal use of V forms is the main strategy to convey respect and distance. They also show that a frequent practice is the non-reciprocal use of pronouns (Ön/Maga/te) and the comb inat i on of l ex i ca l forms encod ing var i ous degrees of social distance. The analysis points out that address practices in this community are shaped by the following factors: the hierarchical, role-dependent nature of the teacher-student relationship, the role of solidarity in joint work activities, and the adaptation of individual address repertoires to the norms of the practice community. The paper demonstrates that the non-reciprocal use of address forms does not indicate a high degree of hierarchy, but rather different ideologies and interpretations of address practices on the part of students and teachers.

TCR repertoire characteristics predict clinical response to adoptive CTL therapy against nasopharyngeal carcinoma

ABSTRACT The past decade has witnessed the gradual and steady progress of adoptive T cell therapy in treating various types of cancer. In combination with gemcitabine and carboplatin chemotherapy, we previously conducted a clinical trial, NCT00690872, to treat Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) patients with autologous EBV-expanded cytotoxic T lymphocytes (CTLs). While achieving a 2-year overall survival rate of 62.9%, this trial failed to induce an anti-tumor response in a sizable fraction of patients. Thus, the identification of benchmarks capable of evaluating CTL products and predicting clinical immunotherapeutic efficacy remains an urgent need. We conducted T cell receptor (TCR) repertoire sequencing to assess EBV-expanded infusion-ready CTL products. To depict the overall repertoire landscape, we evaluated the individual repertoire diversity by Shannon entropy, and, compared the inter-patient CDR3 similarity to estimate T cells expanded by common antigens. With a recently developed bioinformatics algorithm, termed Motif Analysis, we made a machine-learning prediction of structural regions within the CDR3 of TCRβ that associate with CTL therapy prognosis. We found that long term survivors, defined as patients surviving longer than two years, had a higher CTL repertoire diversity with reduced inter-patient similarity. Furthermore, TCR Motif Analysis identified 11 structural motifs distinguishing long term survivors from short term survivors. Specifically, two motifs with a high area under the curve (AUC) values were identified as potential predictive benchmarks for efficacious CTL production. Together, these results reveal that the presence of diverse TCR sequences containing a common core motif set is associated with a favorable response to CTL immunotherapy against EBV-positive NPC.

Examining the relation between students’ active engagement in shared metacognitive regulation and individual learner characteristics

The study investigates whether individual learner characteristics relate to differences in university students’ engagement in socially shared metacognitive regulation (SSMR) when tutoring peers. Students’ motivation for learning, self-efficacy for learning and regulation, feeling of relatedness to peers, and individual repertoire of metacognitive regulation skills are included. SSMR was analysed through systematic observation of video recorded tutoring sessions (22.5 hours). The study involved 73 students, who further completed questionnaires and a think-aloud task. Multilevel models were run to investigate the relation between individual learner characteristics and students’ involvement in SSMR. The results revealed that only students’ adoption of metacognitive regulation during individual learning and their self-efficacy for regulation are significant correlates of their engagement in SSMR.

The multilingual workplace realities of Polish truckers: A case study in the Netherlands

AbstractAlthough international truckers are essential to the European supply chain, we know little about how they deal with their frequent multilingual workplace interactions. This paper examines the effects of participants’ Individual Multilingual Repertoires (Pitzl, Marie-Luise. 2016. World Englishes and creative idioms in English as a lingua franca.World Englishes35(2). 293–309.https://doi.org/10.1111/weng.12196) on their behavior and attitude toward multilingual interactions. Five Polish truckers and six Dutch logistics professionals were observed and interviewed. An ethnographic case study approach allowed us to consider interactions from multiple perspectives. Findings from the study reveal that some, but not all, Polish truckers struggle to interact in the most common lingua francas in the Netherlands: English and German. We show that some of the Dutch logistics professionals have a low opinion of foreign drivers’ linguistic abilities, which impairs the potential to find shared multilingual resources, and ultimately to improve communication skills. Results of the study contribute to an understanding of the dynamics of multilingual interactions in the workplace. Practical suggestions for logistics professionals and future research are identified.

Landscape of Public T Cell Receptors Associated with Recovery from COVID-19

T cells play an essential role in COVID-19, but characteristics of beneficial clones remain unclear. By analysis of clonal trajectories, we identified recovery-associated expanding T cell clones many of which carrying public T cell receptors (TCRs). Mining the immune repertoires of unrelated COVID-19 cases for these sequences revealed T cells with exact TCR complementarity-determining region 3 identity that were more abundant in recovering than in fatal cases. These TCRs were also found in subjects not previously exposed to the virus, with lower representation in repertoires from risk groups like aged individuals or cancer patients. Together, our data indicate that a significant part of the recovery-associated T cell response in COVID-19 may be mediated by public TCRs that are present in repertoires of unexposed individuals. The lower representation of these clones in repertoires of risk groups or failure to expand such clones may contribute to more unfavorable clinical COVID-19 courses.Funding: This project was partially funded by the CRC 841 of the German Research Foundation (toMB) as well as by the Martin-Luther-University Halle (Saale).Conflict of Interest: The authors declare no competing interests.Ethical Approval: Blood collection of COVID-19 patients was performed under institutional review board approvals number 2020-039 and 11/17. Blood collection of pre-pandemic samples was performed under approval of ethics committee of the medical association Hamburg (project number PV4767) and the ethics committee of the medical faculty of MartinLuther-University Halle-Wittenberg (project number 2014-75). Written informed consent was received from all participants. The study has been performed in accordance with the declaration of Helsinki of 1975.

Valutare per includere Il valore dei repertori linguistici plurali

This contribution illustrates a proposal for an inclusive plurilingual assessment, analysing the construct of plurilingual competence and the concept of intercomprehension between Romance languages. It also presents data from the first examination sessions of an innovative plurilingual test, developed within the EVAL-IC Erasmus+ project to assess intercomprehension competence among the five Romance languages of the project (Portuguese, Spanish, Italian, French and Romanian). It focuses on the written receptive dimension of intercomprehension, proving that a single test can highlight the value of the pluralistic repertoire of individuals.

Behavioral Analysis of Law: An Operant Interpretation of Legal Systems


 Law is interpreted as a functionally specialized social system, selected by its consequences, whose main function is to control politically defined socially undesirable behavior. Such control derives from legal norms, which are interlocked behavioral patterns, controlled by changes in the probability of application of sanctions, that establish social contingencies of reinforcement to the behavior of group members. These behavioral patterns form a legal behavioral network, in each node of which one response emitted by one person produces discriminative stimuli to the response of a second person, which, in turn, reinforces the occurrence of the first response and generates discriminative stimuli for the behavior of other individuals that take part in subsequent nodes. A great part of behavioral patterns that form legal norms consist of rule uttering responses, occurring in problem-solving contexts, which are verbal responses reinforced by changes in the repertoire of other individuals related to the probability of application of sanctions. Legal rules are composed of three elements: relevant factual assumptions, social goal and legal contingency. This behavior-analytic interpretation of legal systems, which proposes a novel naturalistic legal theory, encourages new areas of empirical research and applications.

Influence of environmental enrichment on the behavior of captive Ateles paniscus (Primates: Atelidae) in the Parque Zoobotânico Getúlio Vargas, Salvador, Bahia, Brazil

Técnicas de enriquecimento ambiental tornam o ambiente cativo mais interessante e agradável para os animais, aumentando o bem-estar e prevenindo o desenvolvimento de comportamentos anormais. Nesta pesquisa, avaliamos a influência de diferentes técnicas de enriquecimento no comportamento de dois indivíduos de Ateles paniscus mantidos cativos no Parque Zoobotânico Getúlio Vargas, Salvador, Brasil. O estudo foi dividido em cinco fases: controle; enriquecimento sensorial; enriquecimento social; enriquecimento alimentar e pós-enriquecimento. O método animal-focal com registro instantâneo foi utilizado para registrar os atos comportamentais exibidos nas diferentes fases de enriquecimento e estes foram comparados, quanto à sua frequência, com os exibidos na fase controle. Também foi comparada a frequência de uso dos artefatos introduzidos no recinto durante as fases sensorial e alimentar. De modo geral, não houve diferenças entre os atos comportamentais exibidos nas diferentes fases de enriquecimento, exceto durante a fase de enriquecimento alimentar do macho. Também não houve diferenças quanto ao uso dos artefatos. Contudo, os resultados evidenciam a influência de um ambiente enriquecido sobre a frequência de ocorrência dos comportamentos dos indivíduos. É possível que as condições do recinto e a presença dos visitantes exerçam influências negativas no comportamento dos indivíduos, de modo a não favorecer a redução efetiva dos comportamentos anormais observado.

Young children as actors of institutional language policies and practices in day care centres

AbstractAs children’s agency in influencing institutional language practices is often not carefully reflected in early childhood education curricula, the objective of this paper is to offer meaningful insights about how institutional language policies are both reproduced and transformed by children’s everyday use of language. For this purpose, we will combine conceptual resources from social theory, sociolinguistics and childhood studies in order to analyse children’s linguistic behaviour by applying a structure-agency perspective as a relational approach. Drawing on data from ethnographic field research within institutional day care centres in Luxembourg, our findings demonstrate that the status of children as actors in institutional language practices is strongly connected to institutional policies as a structural condition. However, this does not mean that children just enact these language policies, because they are actors of both maintaining, underminingandalternating them. In this respect, especially the translanguaging of children and caregivers plays a crucial role in the Luxembourgish context as it allows to build a bridge between the official institutional language policy and the individual linguistic repertoires. Considering the goal of establishing a plurilingual environment in early childhood education which now is paramount to the educational language policy of the Luxembourgish government, this article suggests that translanguaging practices should be considered as one of the key starting points to create a plurilingual ecology in and through everyday practice in the day care centres.

Genetic and environmental determinants of human TCR repertoire diversity

T cell discrimination of self and non-self is the foundation of the adaptive immune response, and is orchestrated by the interaction between T cell receptors (TCRs) and their cognate ligands presented by major histocompatibility (MHC) molecules. However, the impact of host immunogenetic variation on the diversity of the TCR repertoire remains unclear. Here, we analyzed a cohort of 666 individuals with TCR repertoire sequencing. We show that TCR repertoire diversity is positively associated with polymorphism at the human leukocyte antigen class I (HLA-I) loci, and diminishes with age and cytomegalovirus (CMV) infection. Moreover, our analysis revealed that HLA-I polymorphism and age independently shape the repertoire in healthy individuals. Our data elucidate key determinants of human TCR repertoire diversity, and suggest a mechanism underlying the evolutionary fitness advantage of HLA-I heterozygosity.

Why the Outcome of Anti-Tumor Immune Responses is Heterogeneous: A Novel Idea in the Context of Immunological Heterogeneity in Cancers.

The question as to why some hosts can eradicate their tumors while others succumb to tumor-progression remains unanswered. Here, a provocative concept is proposed that intrinsic differences in the T cell receptor (TCR) repertoire of individuals may influence the outcome of anti-tumor immunity by affecting the frequency and/or variety of tumor-reactive CD8 and/or CD4 tumor-infiltrating lymphocytes. This idea implicates that the TCR repertoire in a given patient might not provide sufficiently different TCR clones that can recognize tumor antigens, namely, "a hole in the TCR repertoire" might exist. This idea may provide a novel perspective to further dissect the mechanisms underlying heterogeneous anti-tumor immune responses in different hosts. Besides tumor-intrinsic heterogeneity and host microbiome, the various factors that may constantly shape the dynamic TCR repertoire are also discussed. Elucidating mechanistic differences in different individuals' immune systems will allow to better harness immune system to design new personalized cancer immunotherapy.