Editors' ChoiceImmunology

Searching for Needles in the T Cell Receptor Haystack

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Science Translational Medicine  20 Nov 2013:
Vol. 5, Issue 212, pp. 212ec191
DOI: 10.1126/scitranslmed.3007982

The diversity and specificity of the adaptive immune system allow us to fight off pathogens with a vast repertoire of distinct B and T cells. The T cell receptor (TCR) confers antigen specificity, but with an estimated 1011 permutations possible in a single individual, the TCR repertoire looks a lot like the proverbial haystack. Linnemann and colleagues present a new method that allows high-throughput identification of TCR sequences and describe several practical applications of this approach.

With this method, the authors isolate individual fragments of genomic DNA that encode specific TCR sequences by using common regions of individual TCRs as “bait.” Then, captured genomic fragments undergo deep sequencing, allowing for the identification of these sequences. This approach was validated by testing T cells with a known viral specificity and subsequently used to explore several potentially clinical relevant scenarios. In one example, the authors evaluated the repertoire of TCRs present within a single melanoma tumor isolated from a patient. Taking the bulk population of T cells and selecting for those that react to autologous tumor by up-regulating the activation marker CD107a, they identified several dominant clones that show functional activity against the tumor in vitro. One of the dominant clones was also detectable in a matched peripheral blood sample. With this proof of principle, the authors are well positioned to ask some very interesting questions about how the TCR repertoire may change over time during tumor development, in relation to antitumor therapies, and as the tumor adapts or evades the immune system.

TCR specificity is one piece of the puzzle in understanding the complexity of immune responses against pathogens and tumors. Understanding how TCR repertoire relates to human disease requires tools to robustly track TCR specificities in human samples. Linnemann et al. present an approach that can help to sort through the haystack and start to make sense of TCR specificities in clinically relevant settings.

C. Linnemann et al., High-throughput identification of antigen-specific TCRs by TCR gene capture. Nat. Med. 19, 1534–1541 (2013). [Abstract]

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