Balancing sensitivity and specificity in distinguishing TCR groups by CDR sequence similarity

Neerja Thakkar,Chris Bailey-Kellogg

doi:10.1186/s12859-019-2864-8

Abstract

BackgroundRepertoire sequencing is enabling deep explorations into the cellular immune response, including the characterization of commonalities and differences among T cell receptor (TCR) repertoires from different individuals, pathologies, and antigen specificities. In seeking to understand the generality of patterns observed in different groups of TCRs, it is necessary to balance how well each pattern represents the diversity among TCRs from one group (sensitivity) vs. how many TCRs from other groups it also represents (specificity). The variable complementarity determining regions (CDRs), particularly the third CDRs (CDR3s) interact with major histocompatibility complex (MHC)-presented epitopes from putative antigens, and thus encode the determinants of recognition.ResultsWe here systematically characterize the predictive power that can be obtained from CDR3 sequences, using representative, readily interpretable methods for evaluating CDR sequence similarity and then clustering and classifying sequences based on similarity. An initial analysis of CDR3s of known structure, clustered by structural similarity, helps calibrate the limits of sequence diversity among CDRs that might have a common mode of interaction with presented epitopes. Subsequent analyses demonstrate that this same range of sequence similarity strikes a favorable specificity/sensitivity balance in distinguishing twins from non-twins based on overall CDR3 repertoires, classifying CDR3 repertoires by antigen specificity, and distinguishing general pathologies.ConclusionWe conclude that within a fairly broad range of sequence similarity, matching CDR3 sequences are likely to share specificities.

Highlights

Repertoire sequencing is enabling deep explorations into the cellular immune response, including the characterization of commonalities and differences among T cell receptor (TCR) repertoires from different individuals, pathologies, and antigen specificities
We study a diverse group of Complementarity determining region (CDR) datasets in order to evaluate in general how predictive TCR sequence is of relationships among groups
As to provide a consistent and interpretable basis for drawing conclusions, as well as to evaluate the information content provided by CDR3 alone, we use only CDR3 for all datasets, and separately analyze CDR3α and CDR3β

Summary

Introduction

Repertoire sequencing is enabling deep explorations into the cellular immune response, including the characterization of commonalities and differences among T cell receptor (TCR) repertoires from different individuals, pathologies, and antigen specificities. The variable complementarity determining regions (CDRs), the third CDRs (CDR3s) interact with major histocompatibility complex (MHC)-presented epitopes from putative antigens, and encode the determinants of recognition. The recognition by T cell receptors (TCRs) of non-self peptide epitopes presented by major histocompatibility complex (MHC) proteins drives the cellular immune response against the non-self offender. In the case of intracellular non-self peptides, e.g., infected or cancerous cells, the ternary MHC:peptide: TCR recognition can lead to the killing of abnormal cells presenting these peptides; in the case of extracellular non-self peptides, e.g., pathogens or biotherapeutics, it can lead to the development of a humoral response to neutralize or clear the antigens containing these peptides. TCRs are much more diverse, with hypervariable complementarity determining regions (CDRs), the third CDRs (CDR3s), which are Thakkar and Bailey-Kellogg BMC Bioinformatics (2019) 20:241

Methods

Results

Conclusion