Spatial maps of T cell receptors and transcriptomes reveal distinct immune niches and interactions in the adaptive immune response

• Published in: Immunity (Cambridge, Mass.) Mass.), 2022-10, Vol.55 (10), p.1940-1952.e5
• Main Authors: Liu, Sophia, Iorgulescu, J. Bryan, Li, Shuqiang, Borji, Mehdi, Barrera-Lopez, Irving A., Shanmugam, Vignesh, Lyu, Haoxiang, Morriss, Julia W., Garcia, Zoe N., Murray, Evan, Reardon, David A., Yoon, Charles H., Braun, David A., Livak, Kenneth J., Wu, Catherine J., Chen, Fei
• Format: Article
• Language: English
• Subjects: Adaptive Immunity - genetics; Animals; cell interactions; clonotype; Humans; immune niches; Mice; Receptors, Antigen, T-Cell; sequencing; spatial; T cell; T cell receptor; T-Lymphocytes; tertiary lymphoid structures; Transcriptome; transcriptomics; tumor infiltrating lymphocytes
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2022.09.002

T cells mediate antigen-specific immune responses to disease through the specificity and diversity of their clonotypic T cell receptors (TCRs). Determining the spatial distributions of T cell clonotypes in tissues is essential to understanding T cell 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 T cells and their receptors in mouse spleen. In human lymphoid germinal centers, we identified spatially distinct TCR repertoires. Profiling T cells in renal cell carcinoma and melanoma specimens revealed heterogeneous immune responses: T cell 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 T cell responses. [Display omitted] •Slide-TCR-seq measures the location, clonotype, and gene expression of T cells•Germinal centers in human lymph nodes and tonsil have spatially segregated T clones•Cancers can show spatial and transcriptomic inter- and intra-clonotype heterogeneity•Expression profiles differ between T clones in neighboring monocytes and tumor cells T cells’ location, clonotype, and gene expression are critical to understanding immune responses. Liu, Iorgulescu, Li, and colleagues developed Slide-TCR-seq to simultaneously study spatial and transcriptomic differences between T cell clones with a 10-μm resolution and applied it to human lymphoid organs and cancer contexts.