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Location matters: mapping antigen receptors within tissues

Nature Reviews Immunology volume 24, page 617 (2024)Cite this article

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B cells and T cells develop, differentiate and expand by tightly orchestrated processes that occur in spatially distinct sites across the body. How these events play out strongly affects our ability to respond to pathogens, vaccines and tumours and maintain self-tolerance. B cells and T cells express antigen receptors, which are formed by somatic recombination during development, are clonally inherited and give each clone a unique molecular specificity. Determining the spatial distribution of B cell or T cell clones within their microenvironment has been technically challenging, especially in human tissues, but is important to understand clonal selection, expansion and persistence.

There are many considerations to applying Spatial VDJ. First, Spatial VDJ obtains the full-length nucleotide sequence, which reveals information, such as somatic hypermutation events, that are not attainable by probe-based methods that require a priori sequence information. Second, Spatial VDJ does not require expensive infrastructure; thus, it is accessible to most users with standard laboratory equipment. Third, Spatial VDJ is based on polyA-capture and enrichment of the receptor constant segments, rather than highly polymorphic VDJ genes, which likely reduces clone-specific biases. Because the protocol captures antigen receptor transcripts, it is sensitive to their expression level per cell, which varies between cell subsets. The upstream cDNA is not at single-cell resolution, and areas between the spots in the capture array will not be assayed. Consequently, Spatial VDJ is not quantitative with respect to cell numbers per clone within a spot, and there is likely to be a detection bias that depends on cell subset as well as clone size. Combined, this means that smaller clones are more challenging to detect. To obtain paired receptor sequences for functional tests, it is beneficial to have matched single-cell data, as computational pairing remains challenging in cellularly dense tissues. At present, there are many technological and computational efforts to extend the methodology.

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References

  1. Engblom, C. et al. Spatial transcriptomics of B cell and T cell receptors reveals lymphocyte clonal dynamics. Science 382, eadf8486 (2023).

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Authors and Affiliations

  1. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden

    Qirong Lin

  2. SciLifeLab, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden

    Kim Thrane

  3. SciLifeLab, Department of Medicine Solna, Center of Molecular Medicine, Karolinska Institute and University Hospital, Stockholm, Sweden

    Camilla Engblom

Authors
  1. Qirong Lin
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  2. Kim Thrane
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  3. Camilla Engblom
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Corresponding author

Correspondence to Camilla Engblom.

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Competing interests

C.E., K.T. and Q.L. are inventors on a US patent (US11692218B2) and scientific consultants for 10x Genomics Inc., which holds intellectual property rights to this spatial technology.

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Lin, Q., Thrane, K. & Engblom, C. Location matters: mapping antigen receptors within tissues. Nat Rev Immunol 24, 617 (2024). https://doi.org/10.1038/s41577-024-01069-7

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