Dissecting cellular crosstalk by sequencing physically interacting cells

Nat Biotechnol. 2020 May;38(5):629-637. doi: 10.1038/s41587-020-0442-2. Epub 2020 Mar 9.


Crosstalk between neighboring cells underlies many biological processes, including cell signaling, proliferation and differentiation. Current single-cell genomic technologies profile each cell separately after tissue dissociation, losing information on cell-cell interactions. In the present study, we present an approach for sequencing physically interacting cells (PIC-seq), which combines cell sorting of physically interacting cells (PICs) with single-cell RNA-sequencing. Using computational modeling, PIC-seq systematically maps in situ cellular interactions and characterizes their molecular crosstalk. We apply PIC-seq to interrogate diverse interactions including immune-epithelial PICs in neonatal murine lungs. Focusing on interactions between T cells and dendritic cells (DCs) in vitro and in vivo, we map T cell-DC interaction preferences, and discover regulatory T cells as a major T cell subtype interacting with DCs in mouse draining lymph nodes. Analysis of T cell-DC pairs reveals an interaction-specific program between pathogen-presenting migratory DCs and T cells. PIC-seq provides a direct and broadly applicable technology to characterize intercellular interaction-specific pathways at high resolution.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Animals, Newborn
  • Cell Communication
  • Cells, Cultured
  • Computational Biology
  • Dendritic Cells / chemistry
  • Dendritic Cells / cytology*
  • Female
  • Flow Cytometry
  • Gene Expression Profiling / methods*
  • Lung / chemistry
  • Lung / cytology
  • Mice
  • Sequence Analysis, RNA
  • Single-Cell Analysis / methods*
  • T-Lymphocytes / chemistry
  • T-Lymphocytes / cytology*