OLGA: fast computation of generation probabilities of B- and T-cell receptor amino acid sequences and motifs

Sethna, Zachary; Elhanati, Yuval; Callan, Curtis G.; Walczak, Aleksandra M.; Mora, Thierry

doi:10.1093/bioinformatics/btz035

Cited by 173 publications

(266 citation statements)

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“…We tested this by directly calculating the generation probability of amino acid sequences in the CDR3 to determine if the public clonotypes are easier to generate than the private at both time points, acute and convalescent. This allowed a direct and rigorously quantitative test of whether the expanded persistent public clonotypes were of higher generation probability (39,42). The TCR sequences used by dominant public TCRAV of either GLC-BM-or YVL-BR-specific responses have a significantly greater probability of generation while only the GLC-BM TCRBV public but not the YVL-BR public repertoire has a greater probability of being generated (Fig.…”

Section: Resultsmentioning

confidence: 99%

Epstein-Barr Virus Epitope–Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor α and β Repertoires

Gil

Kamga

Chirravuri-Venkata

et al. 2020

mBio

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Recognition modes of individual T cell receptors (TCRs) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of Epstein-Barr virus (EBV)-specific clonotypes in acute infectious mononucleosis (AIM). Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse “de novo” clonotypes. The persistent clonotypes had a greater probability of being generated than nonpersistent clonotypes due to convergence recombination of multiple nucleotide sequences to encode the same amino acid sequence, as well as the use of shorter complementarity-determining regions 3 (CDR3s) with fewer nucleotide additions (i.e., sequences closer to germ line). Moreover, the two most immunodominant HLA-A2-restricted EBV epitopes, BRLF1109 and BMLF1280, show highly distinct antigen-specific public (i.e., shared between individuals) features. In fact, TCRα CDR3 motifs played a dominant role, while TCRβ played a minimal role, in the selection of TCR repertoire to an immunodominant EBV epitope, BRLF1. This contrasts with the majority of previously reported repertoires, which appear to be selected either on TCRβ CDR3 interactions with peptide/major histocompatibility complex (MHC) or in combination with TCRα CDR3. Understanding of how TCR-peptide-MHC complex interactions drive repertoire selection can be used to develop optimal strategies for vaccine design or generation of appropriate adoptive immunotherapies for viral infections in transplant settings or for cancer. IMPORTANCE Several lines of evidence suggest that TCRα and TCRβ repertoires play a role in disease outcomes and treatment strategies during viral infections in transplant patients and in cancer and autoimmune disease therapy. Our data suggest that it is essential that we understand the basic principles of how to drive optimum repertoires for both TCR chains, α and β. We address this important issue by characterizing the CD8 TCR repertoire to a common persistent human viral infection (EBV), which is controlled by appropriate CD8 T cell responses. The ultimate goal would be to determine if the individuals who are infected asymptomatically develop a different TCR repertoire than those that develop the immunopathology of AIM. Here, we begin by doing an in-depth characterization of both CD8 T cell TCRα and TCRβ repertoires to two immunodominant EBV epitopes over the course of AIM, identifying potential factors that may be driving their selection.

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Section: Resultsmentioning

confidence: 99%

Epstein-Barr Virus Epitope–Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor α and β Repertoires

Gil

Kamga

Chirravuri-Venkata

et al. 2020

mBio

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“…We observed uniquely biased V-J usage for each epitope and found that the combined V and J genes in ID clones were largely shared with the SD responses (data not shown). To predict the generation probabilities of ID and SD responses (based on their VDJ recombinations), we made use of the OLGA server (Sethna et al 2019). A per-epitope comparison of the generation probabilities for ID and SD responses did not indicate a significant difference, suggesting that the immunodominance of a T cell clone cannot be explained by high generation probability of its TCR sequence.…”

Section: Discussionmentioning

confidence: 99%

Revealing factors determining immunodominant responses against dominant epitopes

2019

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Upon recognition of peptide-MHC complexes by T cell receptors (TCR), the cognate T cells expand and differentiate into effector T cells to generate protective immunity. Despite the fact that any immune response generates a diverse set of TCR clones against a particular epitope, only a few clones are highly expanded in any immune response. Previous studies observed that the highest frequency clones usually control viral infections better than subdominant clones, but the reasons for this dominance among T cell clones are still unclear. Here, we used publicly available TCR amino acid sequences to study which factors determine whether a response becomes immunodominance (ID) per donor; we classified the largest T cell clone as the epitope-specific dominant clone and all the other clones as subdominant responses (SD). We observed a distinctively hydrophobic CDR3 in ID responses against a dominant epitope from influenza A virus, compared to the SD responses. The common V-J combinations were shared between ID and SD responses, suggesting that the biased V-J recombination events are restricted by epitope specificity; thus, the immunodominance is not directly determined by a bias combination of V and J genetic segments. Our findings reveal a close similarity of global sequence properties between dominant and subdominant clones of epitope-specific responses but detectable distinctive amino acid enrichments in ID. Taken together, we believe this first comparative study of immunodominant and subdominant TCR sequences can guide further studies to resolve factors determining the immunodominance of antiviral as well as tumor-specific T cell responses.

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“…Combinatorial pairing of heavy and light chains yields a theoretical diversity of about 2.9 × 10 6 different antibodies. Including the P/N nucleotides, the theoretical number of different antibody sequences is vastly higher than the total number of estimated B cells in the human body (10 12 ) [9]. However, all those antibody sequences are not equally likely to be generated.…”

Section: Introductionmentioning

confidence: 99%

“…However, all those antibody sequences are not equally likely to be generated. Their generation probability spans 30 orders of magnitude for IgH alone [9,10], with additional diversity being generated by insertions and deletions [11]. Of note, due to sampling issues, the number of B cell clones whose size falls below the detection threshold is unknown, rendering estimates of total B cell counts unreliable [12,13].…”

Section: Introductionmentioning

confidence: 99%

Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies

et al. 2020

Self Cite

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The human antibody repertoire is generated by the recombination of different gene segments as well as by processes of somatic mutation. Together these mechanisms result in a tremendous diversity of antibodies that are able to combat various pathogens including viruses and bacteria, or malignant cells. In this review, we summarize the opportunities and challenges that are associated with the analyses of the B cell receptor repertoire and the antigen-specific B cell response. We will discuss how recent advances have increased our understanding of the antibody response and how repertoire analyses can be exploited to inform on vaccine strategies, particularly against HIV-1.Antibodies are composed of heavy and light chains, both of which are divided into a constant and a variable region ( Figure 1a). The different isotypes for the heavy chain constant regions mediate different effector functions and are grouped into the classes IgM, IgD, and IgE [3]. The variable regions of heavy and light chains form the paratope that contacts the epitope on a particular antigen (e.g., on a bacterial or viral surface protein). Two essential steps act during the lifespan of a B cell to generate B cell receptor diversity: (i) the V(D)J recombination process that builds the naïve (i.e., antigen-inexperienced) B cell repertoire, and (ii) somatic hypermutation (SHM) during the process of affinity maturation that generates high affinity B cell receptors and antibodies (i.e., the antigen-experienced repertoire).lifespan of a B cell to generate B cell receptor diversity: i.) the V(D)J recombination process that 52 builds the naïve (i.e., antigen-inexperienced) B cell repertoire, and ii.) somatic hypermutation (SHM) 53 during the process of affinity maturation that generates high affinity B cell receptors and antibodies 54 (i.e., the antigen-experienced repertoire). 55The initial diversity of the B cell repertoire results from the assembly of the B cell receptor 56 during early B cell development in the bone marrow. The recombination-activating gene (RAG) 1/2 57 enzymes recombine variable (V), diversity (D), and joining (J) gene segments of the immunoglobulin 58 heavy (IgH) chain locus to first assemble the heavy chain variable region, followed by V and J gene 59 segment recombination within the Ig kappa (IgK) and Ig lambda (IgL) loci [4]. Junctional diversity is 60 further increased by RAG1/2 and other enzymes through the generation of palindromic (P) 61 nucleotides, as well as by the terminal deoxynuclotidyl transferase (TdT) through the addition of 62 non-template (N) nucleotides [5] (Figure 1b). Heavy and light chain V genes exclusively encode for 63 two complementarity determining regions (CDR1 and CDR2) that are usually structurally exposed 64 at the tip of the antibody and contribute to antigen recognition. A third CDR (CDR3) is generated by 65 the V(D)J recombination process and is the most variable part within B cell receptors and antibodies. 66The CDRs are interspersed and flanked with framework regions (FWR) that mainly function a...

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OLGA: fast computation of generation probabilities of B- and T-cell receptor amino acid sequences and motifs

Cited by 173 publications

References 50 publications

Epstein-Barr Virus Epitope–Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor α and β Repertoires

Epstein-Barr Virus Epitope–Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor α and β Repertoires

Revealing factors determining immunodominant responses against dominant epitopes

Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies

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