Deciphering the Regulatory Landscape of γδ T Cell Development by Single-Cell RNA-Sequencing

SUMMARY Recent studies have established γδ T cells as critical players in a broad range of infections, antitumor surveillance, autoimmune diseases and tissue homeostasis. However, differentiation of γδ T cells in the adult thymus remains poorly understood, due to the rare frequency of this lineage. Here, we infer high-resolution developmental trajectories of this rare population by single-cell RNA-sequencing. We reveal previously unknown subtypes and identify the transcription factor c-MAF as a novel key regulator of IL-17-producing γδ T cell ( γδ T17) differentiation. c-MAF knockout mice exhibit a complete block in γδ T17 differentiation, absence of these cells from peripheral organs, and protection from an autoimmune phenotype in a psoriasis model. Single-cell RNA-sequencing of Sox13 and Rorc knockout mice pinpoints c-MAF as an essential missing link between these lineage-specifying factors. These findings significantly enhance our understanding of γδ T cell ontogeny. Our experimental strategy provides a blueprint for deciphering differentiation of rare cell types.