220 research outputs found
Human thymic T cell repertoire is imprinted with strong convergence to shared sequences
A highly diverse repertoire of T cell antigen receptors (TCR) is created in the thymus by recombination of gene segments and the insertion or deletion of nucleotides at the junctions. Using next-generation TCR sequencing we define here the features of recombination and selection in the human TCR alpha and TCR beta locus, and show that a strikingly high proportion of the repertoire is shared by unrelated individuals. The thymic TCRa nucleotide repertoire was more diverse than TCR beta, with 4.1 x 10(6) vs. 0.81 x 10(6) unique clonotypes, and contained nonproductive clonotypes at a higher frequency (69.2% vs. 21.2%). The convergence of distinct nucleotide clonotypes to the same amino acid sequences was higher in TCRa than in TCR beta repertoire (1.45 vs. 1.06 nucleotide sequences per amino acid sequence in thymus). The gene segment usage was biased, and generally all individuals favored the same genes in both TCR alpha and TCR beta loci. Despite the high diversity, a large fraction of the repertoire was found in more than one donor. The shared fraction was bigger in TCR alpha than TCR beta repertoire, and more common in in-frame sequences than in nonproductive sequences. Thus, both biases in rearrangement and thymic selection are likely to contribute to the generation of shared repertoire in humans.Peer reviewe
The Changing Landscape of Naive T Cell Receptor Repertoire With Human Aging
Human aging is associated with a profound loss of thymus productivity, yet naïve T lymphocytes still maintain their numbers by division in the periphery for many years. The extent of such proliferation may depend on the cytokine environment, including IL-7 and T-cell receptor (TCR) “tonic” signaling mediated by self pMHCs recognition. Additionally, intrinsic properties of distinct subpopulations of naïve T cells could influence the overall dynamics of aging-related changes within the naïve T cell compartment. Here, we investigated the differences in the architecture of TCR beta repertoires for naïve CD4, naïve CD8, naïve CD4+CD25−CD31+ (enriched with recent thymic emigrants, RTE), and mature naïve CD4+CD25−CD31− peripheral blood subsets between young and middle-age/old healthy individuals. In addition to observing the accumulation of clonal expansions (as was shown previously), we reveal several notable changes in the characteristics of T cell repertoire. We observed significant decrease of CDR3 length, NDN insert, and number of non-template added N nucleotides within TCR beta CDR3 with aging, together with a prominent change of physicochemical properties of the central part of CDR3 loop. These changes were similar across CD4, CD8, RTE-enriched, and mature CD4 subsets of naïve T cells, with minimal or no difference observed between the latter two subsets for individuals of the same age group. We also observed an increase in “publicity” (fraction of shared clonotypes) of CD4, but not CD8 naïve T cell repertoires. We propose several explanations for these phenomena built upon previous studies of naïve T-cell homeostasis, and call for further studies of the mechanisms causing the observed changes and of consequences of these changes in respect of the possible holes formed in the landscape of naïve T cell TCR repertoire
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
Precise tracking of vaccine-responding T-cell clones reveals convergent and personalized response in identical twins
T-cell receptor (TCR) repertoire data contain information about infections
that could be used in disease diagnostics and vaccine development, but
extracting that information remains a major challenge. Here we developed a
statistical framework to detect TCR clone proliferation and contraction from
longitudinal repertoire data. We applied this framework to data from three
pairs of identical twins immunized with the yellow fever vaccine. We identified
500-1500 responding TCRs in each donor and validated them using three
independent assays. While the responding TCRs were mostly private, albeit with
higher overlap between twins, they could be well predicted using a classifier
based on sequence similarity. Our method can also be applied to samples
obtained post-infection, making it suitable for systematic discovery of new
infection-specific TCRs in the clinic
Genesis of the alpha beta T-cell receptor
The T-cell (TCR) repertoire relies on the diversity of receptors composed of
two chains, called and , to recognize pathogens. Using results
of high throughput sequencing and computational chain-pairing experiments of
human TCR repertoires, we quantitively characterize the
generation process. We estimate the probabilities of a rescue recombination of
the chain on the second chromosome upon failure or success on the first
chromosome. Unlike chains, chains recombine simultaneously on
both chromosomes, resulting in correlated statistics of the two genes which we
predict using a mechanistic model. We find that of cells express
both chains. We report that clones sharing the same chain but
different chains are overrepresented, suggesting that they respond to
common immune challenges. Altogether, our statistical analysis gives a complete
quantitative mechanistic picture that results in the observed correlations in
the generative process. We learn that the probability to generate any
TCR is lower than and estimate the generation diversity
and sharing properties of the TCR repertoire
OLGA: fast computation of generation probabilities of B- and T-cell receptor amino acid sequences and motifs
Motivation: High-throughput sequencing of large immune repertoires has
enabled the development of methods to predict the probability of generation by
V(D)J recombination of T- and B-cell receptors of any specific nucleotide
sequence. These generation probabilities are very non-homogeneous, ranging over
20 orders of magnitude in real repertoires. Since the function of a receptor
really depends on its protein sequence, it is important to be able to predict
this probability of generation at the amino acid level. However, brute-force
summation over all the nucleotide sequences with the correct amino acid
translation is computationally intractable. The purpose of this paper is to
present a solution to this problem.
Results: We use dynamic programming to construct an efficient and flexible
algorithm, called OLGA (Optimized Likelihood estimate of immunoGlobulin
Amino-acid sequences), for calculating the probability of generating a given
CDR3 amino acid sequence or motif, with or without V/J restriction, as a result
of V(D)J recombination in B or T cells. We apply it to databases of
epitope-specific T-cell receptors to evaluate the probability that a typical
human subject will possess T cells responsive to specific disease-associated
epitopes. The model prediction shows an excellent agreement with published
data. We suggest that OLGA may be a useful tool to guide vaccine design.
Availability: Source code is available at https://github.com/zsethna/OLG
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