Spatial maps of Tcell receptors and transcriptomes reveal distinct immune niches and interactions in the adaptive immune response.

Abstract

T cells mediate antigen-specific immune responses to disease through the specificity and diversity of their clonotypic Tcell receptors (TCRs). Determining the spatial distributions of Tcell clonotypes in tissues is essential to understanding Tcell behavior, but spatial sequencing methods remain unable to profile the TCR repertoire. Here, we developed Slide-TCR-seq, a 10-μm-resolution method, to sequence whole transcriptomes and TCRs within intact tissues. We confirmed the ability of Slide-TCR-seq to map the characteristic locations of Tcells and their receptors in mouse spleen. In human lymphoid germinal centers, we identified spatially distinct TCR repertoires. Profiling Tcells in renal cell carcinoma and melanoma specimens revealed heterogeneous immune responses: Tcell states and infiltration differed intra- and inter-clonally, and adjacent tumor and immune cells exhibited distinct gene expression. Altogether, our method yields insights into the spatial relationships between clonality, neighboring cell types, and gene expression that drive Tcell responses.