B細胞およびT細胞受容体の空間トランスクリプトミクスがリンパ球クローン動態を明らかにする Spatial transcriptomics of B cell and T cell receptors reveals lymphocyte clonal dynamics
Camilla Engblom,Kim Thrane,Qirong Lin,Alma Andersson,Hosein Toosi,Xinsong Chen,Embla Steiner,Chang Lu,Giulia Mantovani,Michael Hagemann-Jensen,Sami Saarenpää,Mattias Jangard,Julio Saez-Rodriguez,Jakob Michaëlsson,Johan Hartman,Jens Lagergren,Jeff E. Mold,Joakim Lundeberg,and Jonas Frisén
Science Published:8 Dec 2023
Although current spatial transcriptomics technologies can locate gene expression within tissues, they are unable to map full-length B cell receptor (BCR) and T cell receptor (TCR) sequences in this context. Engblom et al. developed a method called spatial transcriptomics for variable, diversity, and joining sequences (Spatial VDJ), which spatially annotates full-length immunoglobulin and T cell antigen receptor transcripts in frozen human tissue sections. This approach, which also resolves whole transcriptomes and tissue morphology, results in high-fidelity mapping and spatial lineage tracing of B and T cell clones in both human lymphoid and tumor tissues. This technology has the potential to advance our understanding of lymphocyte spatial dynamics in various clinically relevant phenomena such as infection, vaccination, and cancer. —Seth Thomas Scanlon
B cells and T cells respond to infections and inflammation, regulate tissue homeostasis, and maintain immunological memory. The targeted reactivity of B and T cells is determined by their clonally heritable antigen receptors, encoded by immunoglobulin (IG) and T cell (TR) antigen receptor genes. Spatial analysis of lymphocyte clonality may link specific antigen receptors to their regulatory niche or antigen (tumor-associated, self, or foreign). This, in turn, may help identify and harness antigen-specific clones for therapy.
Single-cell technologies permit the study of antigen receptors at a cellular level but lack spatial resolution. Current spatial transcriptomics methods locate gene expression in tissues, but do not retain full-length antigen receptor sequences. Thus, methodologies that comprehensively map B and T cell receptor sequences within tissues are needed. We therefore developed spatial transcriptomics for variable, diversity, and joining (VDJ) sequences (Spatial VDJ), which spatially resolves full-length IG and TR transcripts, tissue morphology, and the whole transcriptome simultaneously in human tissue.
We developed two versions of Spatial VDJ that are compatible with whole-transcriptome 3′ arrays for frozen human tissue sections: (i) long-read (LR) Spatial VDJ for full-length IG and TR antigen receptor transcripts and (ii) short-read (SR) Spatial VDJ for TR only. For both approaches, we enriched for antigen receptor transcripts using hybridization capture targeting the IG and TR constant regions.
Spatial VDJ captured thousands of B and T cell receptor sequences in human tonsil tissue sections. The antigen receptor distribution matched canonical B and T cell locations and spatial gene expression patterns. Amplified clonal sequences were also confirmed by orthogonal methods, and the LR and SR Spatial VDJ versions to capture TR clones yielded comparable results. We found spatial congruency between paired receptor chains and developed a computational framework that identified IG heavy and light chain receptor pairs validated by single-cell VDJ analysis in human breast cancer. Distinct IG receptors spatially segregated across different tumor-associated areas within the same tumor, opening up the possibility of using Spatial VDJ as a first screen for tumor-associated antibodies.
Spatial VDJ also uncovered B cell clonal family diversity measures within and between distinct B cell follicles (containing germinal centers), which are key sites for B cell clonal expansion and maturation. Spatial phylogenetic analysis of B cell clones identified simultaneous lineage tree branching and geographical spreading to distinct germinal centers.
This study describes a method that allows for full-length antigen receptor mapping within human tissue. Spatial VDJ reveals B and T cell clonal dynamics in both lymphoid and cancer tissue. This includes linking clones to tumor-associated gene expression programs and spatially reconstructing B cell clonal diversity and lineage trajectories across their anatomical niches. Ultimately, Spatial VDJ may be useful to discriminate B and T cell clonal dynamics in the context of infections, vaccination, and anticancer immune responses, with the goal of harnessing antigen-specific clones for engineered cell- and antibody-based therapeutics.
Spatial transcriptomics–based method to map B cell and T cell receptors.
Targeted capture of antigen receptor sequences from spatial transcriptomics gene expression libraries resolves full-length receptor distribution alongside tissue anatomy and whole transcriptome in human tissue sections. Spatial VDJ uncovers B and T cell clonal dynamics, including linking clones to tumor-associated gene expression, pairing receptor chains, and reconstructing spatial B cell lineage trajectories.
The spatial distribution of lymphocyte clones within tissues is critical to their development, selection, and expansion. We have developed spatial transcriptomics of variable, diversity, and joining (VDJ) sequences (Spatial VDJ), a method that maps B cell and T cell receptor sequences in human tissue sections. Spatial VDJ captures lymphocyte clones that match canonical B and T cell distributions and amplifies clonal sequences confirmed by orthogonal methods. We found spatial congruency between paired receptor chains, developed a computational framework to predict receptor pairs, and linked the expansion of distinct B cell clones to different tumor-associated gene expression programs. Spatial VDJ delineates B cell clonal diversity and lineage trajectories within their anatomical niche. Thus, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, providing a platform to harness clonal sequences for therapy.