![]() Immune repertoire sequencing could help to identify the pathogen as demonstrated previously for CMV ( 10). Independently, TCR repertoire information could enable tailored immunization strategies with neoantigens to match the T cell repertoire of a patient ( 6– 8).Īlthough lymphocyte repertoire sequencing for cancer diagnostics and immunotherapy has become widespread, its use for diagnosis and prognosis of infectious diseases has not been established yet ( 9). Furthermore, sequencing can be used to track the expansion of the neo-antigen specific clones and thereby the success of cancer treatment. More recently, the identification and characterization of cancer neoantigen-specific T cells has highlighted the potential of TCR sequencing for the identification of tumor neoantigen-specific clones for cell therapy. The identified cancer cell's BCR or TCR sequence can later be tracked with high sensitivity during treatment and during remission, in order to assess whether the tumor is controlled ( 5, 6). The transformed immune cells expand exponentially and the presence of a large malignant clone can easily be identified by TCR or BCR sequencing and the cancer type can be confirmed. This has been most evident in the clinical diagnosis of B or T cell cancers. Nevertheless, bulk sequencing of receptors from cell populations have been very informative in capturing expanded clones in the context of disease. Human repertoires are mostly assessed in blood, and depending on the sample volume the “repertoire” is in fact only a small part of the totality of all existing BCRs or TCRs in an individual. The alpha chain, although often not in contact with the antigen and therefore considered less informative ( 4), can confirm clonality and provide more detailed repertoire information. Similarly, the T cell repertoire can be assessed by sequencing the beta chain of the T cell receptor (TCR). Since the same BCR heavy chain can be paired with different light chains (LC), sequencing of the light chain can confirm clonality, based on a unique HC-LC-chain pair per clone, and can provide more detailed information when assessing the breadth of an immune repertoire. In addition, computationally defined thresholds for clonal relationship for high throughput B cell repertoire sequencing data sets have been proposed ( 3). Often, 85% amino acid sequence similarity is used as a simple inclusion criteria ( 2). ![]() The same variable (V) and joining (J) gene, the same length and a high similarity in the heavy chain CDR3 nucleotide sequence are generally used as criteria to define clonal relationship ( 1). A clone can also include B cells that have a similar but not identical BCRs due to somatic hypermutation. A B cell clone includes all B cells originating from one parent B cell that share the same heavy and light chain variable region nucleotide sequences. The B cell immune repertoire can be analyzed quantitatively and qualitatively by sequencing the re-arranged variable region of the heavy chain (HC) of the B cell receptor (BCR) that is unique for each individual B cell or clonally expanded B cell ( Figure 1). Finally, possible short- and long- term implications for vaccine research are highlighted. Current and potential future applications of single cell technology in immune repertoire analysis are then discussed. This review summarizes recent evidence of converging sequences in infectious diseases. This has enabled the cloning of receptors and the functional validation of a predicted specificity. However, only single cell technologies have made it possible to capture the sequence of both heavy and light chains of a BCR or the alpha and beta chains the TCR. Bulk sequencing has shown putatively specific converging sequences after infection or vaccination. In addition, vaccine testing could be simplified if we could predict responses through sequencing BCR and TCRs. Assuming that it is possible to predict which B and T cell receptors will respond to a given immunogen, vaccine strategies could be optimized and personalized. Repertoire diversity may in these cases be a limiting factor for vaccine efficacy. However, there are indications that there are “holes” in the breadth of repertoire diversity, where no or few B or T cell are able to bind to a given antigen. Traditional vaccine development builds on the assumption that healthy individuals have virtually unlimited antigen recognition repertoires of receptors in B cells and T cells. Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore.
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