Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program

Mesenteric lymph node (mLN) T cells undergo tissue adaptation upon migrating to intestinal lamina propria and epithelium, ensuring appropriate balance between tolerance and resistance. By combining mouse genetics with single-cell and chromatin analyses, we uncovered the molecular imprinting of gut epithelium on T cells. Transcriptionally, conventional and regulatory (T-reg) CD4(+) T cells from mLN, lamina propria and intestinal epithelium segregate based on the gut layer they occupy; trajectory analysis suggests a stepwise loss of CD4 programming and acquisition of an intraepithelial profile. T-reg cell fate mapping coupled with RNA sequencing and assay for transposase-accessible chromatin followed by sequencing revealed that the T-reg cell program shuts down before an intraepithelial program becomes fully accessible at the epithelium. Ablation of CD4-lineage-defining transcription factor ThPOK results in premature acquisition of an intraepithelial lymphocyte profile by mLN T-reg cells, partially recapitulating epithelium imprinting. Thus, coordinated replacement of the circulating lymphocyte program with site-specific transcriptional and chromatin changes is necessary for tissue imprinting. Mucida and colleagues examine how the gut epithelial microenvironment alters CD4(+) T cells during their conversion into intraepithelial lymphocytes. They reveal a stepwise process involving chromatin accessibility and transcription changes triggered by ThPOK downregulation.

Automated summary

The study demonstrates that mesenteric lymph node T cells undergo tissue adaptation upon migrating to intestinal lamina propria and epithelium, with changes in transcription and chromatin. Cells occupying different gut layers have specific CD4 programming, and the transition to intraepithelial lymphocytes involves the shutdown of the T-reg cell program before accessibility to epithelium.