Systematic comparative study of computational methods for T-cell receptor sequencing data analysis

Afzal, Saira; Gil-Fariña, Irene; Rinaldi, Gabriel; Ahmad, Shahzad; Kalle, Christof von; Schmidt, Manfred; Fronza, Raffaele

doi:10.1093/bib/bbx111

Cited by 11 publications

(9 citation statements)

References 45 publications

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“…Additionally, Mora and Walczak showed that the Rényi entropy (the mathematical foundation of Hill-Diversity profiles) can be constructed, in some cases, from rank-frequency plots (70) thereby establishing a direct mathematical link between clonal frequency distribution and diversity indices. Another interesting novel diversity analysis method is the clonal plane and the polyclonal monoclonal diversity index developed by Afzal et al (71). Briefly, these two related concepts represent repertoire diversity in a coordinate system spanned by species richness and evenness.…”

Section: Measuring Immune Repertoire Diversitymentioning

confidence: 99%

Computational Strategies for Dissecting the High-Dimensional Complexity of Adaptive Immune Repertoires

et al. 2018

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The adaptive immune system recognizes antigens via an immense array of antigen-binding antibodies and T-cell receptors, the immune repertoire. The interrogation of immune repertoires is of high relevance for understanding the adaptive immune response in disease and infection (e.g., autoimmunity, cancer, HIV). Adaptive immune receptor repertoire sequencing (AIRR-seq) has driven the quantitative and molecular-level profiling of immune repertoires, thereby revealing the high-dimensional complexity of the immune receptor sequence landscape. Several methods for the computational and statistical analysis of large-scale AIRR-seq data have been developed to resolve immune repertoire complexity and to understand the dynamics of adaptive immunity. Here, we review the current research on (i) diversity, (ii) clustering and network, (iii) phylogenetic, and (iv) machine learning methods applied to dissect, quantify, and compare the architecture, evolution, and specificity of immune repertoires. We summarize outstanding questions in computational immunology and propose future directions for systems immunology toward coupling AIRR-seq with the computational discovery of immunotherapeutics, vaccines, and immunodiagnostics.

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Section: Measuring Immune Repertoire Diversitymentioning

confidence: 99%

Computational Strategies for Dissecting the High-Dimensional Complexity of Adaptive Immune Repertoires

et al. 2018

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“…Thus, exposures to the auto-Ag (Ag1 or Ag2) decreased the diversity of the endogenous Tfh repertoire compared to the PBS group. To establish this finding, we used multiplex iRepertiore PCRs and subsequent MiTCR analysis for preparing libraries and annotating TCRβ sequences ( Bolotin et al, 2013 ), which ensures to yield the highest possible diversity of TCRβ clonotypes ( Afzal et al, 2019 ). To confirm this decrease in diversity of the endogenous Tfh repertoire, we reanalyzed our data for Ag1 with a more precise analysis tool MiXCR that is advantageous for error corrections and adjusts for a more accurate clonal composition ( Bolotin et al, 2013 ; Bolotin et al, 2015 ; Team I, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Receptor repertoires of murine follicular T helper cells reveal a high clonal overlap in separate lymph nodes in autoimmunity

Niebuhr

Belde

Fähnrich

et al. 2021

eLife

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Follicular T helper cells (Tfh) are a specialized subset of CD4 effector T cells that are crucial for germinal center (GC) reactions and for selecting B cells to undergo affinity maturation. Despite this central role for humoral immunity, only few data exist about their clonal distribution when multiple lymphoid organs are exposed to the same antigen (Ag) as it is the case in autoimmunity. Here, we used an autoantibody-mediated disease model of the skin and injected one auto-Ag into the two footpads of the same mouse and analyzed the T cell receptor (TCR)β sequences of Tfh located in GCs of both contralateral draining lymph nodes. We found that over 90% of the dominant GC-Tfh clonotypes were shared in both lymph nodes but only transiently. The initially dominant Tfh clonotypes especially declined after establishment of chronic disease while GC reaction and autoimmune disease continued. Our data demonstrates a dynamic behavior of Tfh clonotypes under autoimmune conditions and emphasizes the importance of the time point for distinguishing auto-Ag-specific Tfh clonotypes from potential bystander activated ones.

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“…RNA was used for RACE-PCR according to previously described protocols [ 57 , 58 ]. List of RACE-PCR oligonucleotides are provided in Table S9 .…”

Section: Methodsmentioning

confidence: 99%

Longitudinal analyses of CLL in mice identify leukemia-related clonal changes including a Myc gain predicting poor outcome in patients

et al. 2021

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Chronic lymphocytic leukemia (CLL) is a B-cell malignancy mainly occurring at an advanced age with no single major genetic driver. Transgenic expression of TCL1 in B cells leads after a long latency to a CLL-like disease in aged Eµ-TCL1 mice suggesting that TCL1 overexpression is not sufficient for full leukemic transformation. In search for secondary genetic events and to elucidate the clonal evolution of CLL, we performed whole exome and B-cell receptor sequencing of longitudinal leukemia samples of Eµ-TCL1 mice. We observed a B-cell receptor stereotypy, as described in patients, confirming that CLL is an antigen-driven disease. Deep sequencing showed that leukemia in Eµ-TCL1 mice is mostly monoclonal. Rare oligoclonality was associated with inability of tumors to develop disease upon adoptive transfer in mice. In addition, we identified clonal changes and a sequential acquisition of mutations with known relevance in CLL, which highlights the genetic similarities and therefore, suitability of the Eµ-TCL1 mouse model for progressive CLL. Among them, a recurrent gain of chromosome 15, where Myc is located, was identified in almost all tumors in Eµ-TCL1 mice. Interestingly, amplification of 8q24, the chromosomal region containing MYC in humans, was associated with worse outcome of patients with CLL.

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Systematic comparative study of computational methods for T-cell receptor sequencing data analysis

Cited by 11 publications

References 45 publications

Computational Strategies for Dissecting the High-Dimensional Complexity of Adaptive Immune Repertoires

Computational Strategies for Dissecting the High-Dimensional Complexity of Adaptive Immune Repertoires

Receptor repertoires of murine follicular T helper cells reveal a high clonal overlap in separate lymph nodes in autoimmunity

Longitudinal analyses of CLL in mice identify leukemia-related clonal changes including a Myc gain predicting poor outcome in patients

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