A novel method for characterizing cell-cell interactions at single-cell resolution reveals unique immune signatures in blood T cell-monocyte complexes during infection (ATB scRNA-Seq)

We designed a novel method to study the transcriptome of single cells forming complexes in a high-throughput fashion, without the need for bioinformatic deconvolution. We applied this method to the study of T cells and monocytes forming complexes in blood isolated from individuals with active tuberculosis, with blood collected at diagnosis and after treatment. We found that the transcriptomic signature of T cells and monocytes forming complexes was associated with TCR/MHC-II immune synaptic features, enrichment for cytotoxic clonally expanded T cells and intermediate monocytes, and - especially at diagnosis - transcriptomic signatures indicating increased immune and metabolic activity. We also found a striking enrichment of “dual-expressing” cells (i.e., co-expressing T cells and monocyte marker genes) in complexes, suggesting RNA exchange occur during T cell-monocyte interactions. Thus, using our novel method, we identified that T cells and monocyte forming complexes in blood hold unique immune signatures distinct from singlets, and that they may be a previously overlooked valuable biomarker to monitor immune synaptic interactions during infection.