Exploring the pre-immune landscape of antigen-specific T cells

Abstract Background Adaptive immune responses to newly encountered pathogens depend on the mobilization of antigen-specific clonotypes from a vastly diverse pool of naive T cells. Using recent advances in immune repertoire sequencing technologies, models of the immune receptor rearrangement process, and a database of annotated T cell receptor (TCR) sequences with known specificities, we explored the baseline frequencies of T cells specific for defined human leukocyte antigen (HLA) class I-restricted epitopes in healthy individuals. Methods We used a database of TCR sequences with known antigen specificities and a probabilistic TCR rearrangement model to estimate the baseline frequencies of TCRs specific to distinct antigens epitopespecificT-cells. We verified our estimates using a publicly available collection of TCR repertoires from healthy individuals. We also interrogated a database of immunogenic and non-immunogenic peptides is used to link baseline T-cell frequencies with epitope immunogenicity. Results Our findings revealed a high degree of variability in the prevalence of T cells specific for different antigens that could be explained by the physicochemical properties of the corresponding HLA class I-bound peptides. The occurrence of certain rearrangements was influenced by ancestry and HLA class I restriction, and umbilical cord blood samples contained higher frequencies of common pathogen-specific TCRs. We also identified a quantitative link between specific T cell frequencies and the immunogenicity of cognate epitopes presented by defined HLA class I molecules. Conclusions Our results suggest that the population frequencies of specific T cells are strikingly non-uniform across epitopes that are known to elicit immune responses. This inference leads to a new definition of epitope immunogenicity based on specific TCR frequencies, which can be estimated with a high degree of accuracy in silico, thereby providing a novel framework to integrate computational and experimental genomics with basic and translational research efforts in the field of T cell immunology

Large-scale template-based structural modeling of T-cell receptors with known antigen specificity reveals complementarity features

IntroductionT-cell receptor (TCR) recognition of foreign peptides presented by the major histocompatibility complex (MHC) initiates the adaptive immune response against pathogens. While a large number of TCR sequences specific to different antigenic peptides are known to date, the structural data describing the conformation and contacting residues for TCR-peptide-MHC complexes is relatively limited. In the present study we aim to extend and analyze the set of available structures by performing highly accurate template-based modeling of these complexes using TCR sequences with known specificity. MethodsIdentification of CDR3 sequences and their further clustering, based on available spatial structures, V- and J-genes of corresponding T-cell receptors, and epitopes, was performed using the VDJdb database. Modeling of the selected CDR3 loops was conducted using a stepwise introduction of single amino acid substitutions to the template PDB structures, followed by optimization of the TCR-peptide-MHC contacting interface using the Rosetta package applications. Statistical analysis and recursive feature elimination procedures were carried out on computed energy values and properties of contacting amino acid residues between CDR3 loops and peptides, using R.ResultsUsing the set of 29 complex templates (including a template with SARS-CoV-2 antigen) and 732 specificity records, we built a database of 1585 model structures carrying substitutions in either TCRα or TCRβ chains with some models representing the result of different mutation pathways for the same final structure. This database allowed us to analyze features of amino acid contacts in TCR - peptide interfaces that govern antigen recognition preferences and interpret these interactions in terms of physicochemical properties of interacting residues.ConclusionOur results provide a methodology for creating high-quality TCR-peptide-MHC models for antigens of interest that can be utilized to predict TCR specificity

VDJdb in 2019: database extension, new analysis infrastructure and a T-cell receptor motif compendium

Here, we report an update of the VDJdb database with a substantial increase in the number of T-cell receptor (TCR) sequences and their cognate antigens. The update further provides a new database infrastructure featuring two additional analysis modes that facilitate database querying and real-world data analysis. The increased yield of TCR specificity identification methods and the overall increase in the number of studies in the field has allowed us to expand the database more than 5-fold. Furthermore, several new analysis methods are included. For example, batch annotation of TCR repertoire sequencing samples allows for annotating large datasets on-line. Using recently developed bioinformatic methods for TCR motif mining, we have built a reduced set of high-quality TCR motifs that can be used for both training TCR specificity predictors and matching against TCRs of interest. These additions enhance the versatility of the VDJdb in the task of exploring T-cell antigen specificities. The database is available at https://vdjdb.cdr3.net

Study of forward Z + jet production in pp collisions at √s=7 TeV

A measurement of the $Z(\rightarrow\mu^+\mu^-)$+jet production cross-section in $pp$ collisions at a centre-of-mass energy $\sqrt{s} = 7$ TeV is presented. The analysis is based on an integrated luminosity of $1.0\,\text{fb}^{-1}$ recorded by the LHCb experiment. Results are shown with two jet transverse momentum thresholds, 10 and 20 GeV, for both the overall cross-section within the fiducial volume, and for six differential cross-section measurements. The fiducial volume requires that both the jet and the muons from the Z boson decay are produced in the forward direction ($2.0<\eta<4.5$). The results show good agreement with theoretical predictions at the second-order expansion in the coupling of the strong interaction.A measurement of the $Z(\rightarrow\mu^+\mu^-)$+jet production cross-section in $pp$ collisions at a centre-of-mass energy $\sqrt{s} = 7$ TeV is presented. The analysis is based on an integrated luminosity of $1.0\,\text{fb}^{-1}$ recorded by the LHCb experiment. Results are shown with two jet transverse momentum thresholds, 10 and 20 GeV, for both the overall cross-section within the fiducial volume, and for six differential cross-section measurements. The fiducial volume requires that both the jet and the muons from the Z boson decay are produced in the forward direction ($2.0<\eta<4.5$). The results show good agreement with theoretical predictions at the second-order expansion in the coupling of the strong interaction

A study of CP violation in B-+/- -&gt; DK +/- and B-+/- -&gt; D pi(+/-) decays with D -&gt; (KSK +/-)-K-0 pi(-/+) final states

A first study of CP violation in the decay modes $B^\pm\to [K^0_{\rm S} K^\pm \pi^\mp]_D h^\pm$ and $B^\pm\to [K^0_{\rm S} K^\mp \pi^\pm]_D h^\pm$, where $h$ labels a $K$ or $\pi$ meson and $D$ labels a $D^0$ or $\overline{D}^0$ meson, is performed. The analysis uses the LHCb data set collected in $pp$ collisions, corresponding to an integrated luminosity of 3 fb$^{-1}$. The analysis is sensitive to the CP-violating CKM phase $\gamma$ through seven observables: one charge asymmetry in each of the four modes and three ratios of the charge-integrated yields. The results are consistent with measurements of $\gamma$ using other decay modes

Measurement of Upsilon production in collisions at root s=2.76 TeV

The production of $\Upsilon(1S)$, $\Upsilon(2S)$ and $\Upsilon(3S)$ mesons decaying into the dimuon final state is studied with the LHCb detector using a data sample corresponding to an integrated luminosity of 3.3 $pb^{-1}$ collected in proton-proton collisions at a centre-of-mass energy of $\sqrt{s}=2.76$ TeV. The differential production cross-sections times dimuon branching fractions are measured as functions of the $\Upsilon$ transverse momentum and rapidity, over the ranges $p_{\rm T} Upsilon(1S) X) x B(Upsilon(1S) -> mu+mu-) = 1.111 +/- 0.043 +/- 0.044 nb, sigma(pp -> Upsilon(2S) X) x B(Upsilon(2S) -> mu+mu-) = 0.264 +/- 0.023 +/- 0.011 nb, sigma(pp -> Upsilon(3S) X) x B(Upsilon(3S) -> mu+mu-) = 0.159 +/- 0.020 +/- 0.007 nb, where the first uncertainty is statistical and the second systematic

Search for CP violation using T-odd correlations in D-0 -&gt; K+K-pi(+)pi(-) decays

A search for $CP$ violation using $T$-odd correlations is performed using the four-body $D^0 \to K^+K^-\pi^+\pi^-$ decay, selected from semileptonic $B$ decays. The data sample corresponds to integrated luminosities of $1.0\,\text{fb}^{-1}$ and $2.0\,\text{fb}^{-1}$ recorded at the centre-of-mass energies of 7 TeV and 8 TeV, respectively. The $CP$-violating asymmetry $a_{CP}^{T\text{-odd}}$ is measured to be $(0.18\pm 0.29\text{(stat)}\pm 0.04\text{(syst)})\%$. Searches for $CP$ violation in different regions of phase space of the four-body decay, and as a function of the $D^0$ decay time, are also presented. No significant deviation from the $CP$ conservation hypothesis is found