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bioRxiv · 10.1101/2020.06.04.134650

Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program

London, M.·Bilate, A. M.·Castro, T. B. R.·Mucida, D.
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Abstract

Mesenteric lymph node (mLN) T cells undergo tissue adaptation upon migrating to intestinal lamina propria (LP) and intraepithelial (IE) compartments, ensuring appropriate balance between tolerance and resistance. By combining mouse genetics with single-cell and chromatin analyses, we addressed the molecular imprinting of gut epithelium on T cells. Transcriptionally, conventional and regulatory (Treg) CD4+ T cells from mLN, LP and IE segregate based on the gut layer they occupy; trajectory analysis suggests a stepwise loss of CD4-programming and acquisition of an intraepithelial profile. Treg fate-mapping coupled with RNA- and ATAC-sequencing revealed that the Treg 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 IEL profile by mLN Tregs, partially recapitulating epithelium imprinting. Thus, coordinated replacement of circulating lymphocyte program with site-specific transcriptional and chromatin changes is necessary for tissue imprinting.

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London, M., Bilate, A. M., Castro, T. B. R., Mucida, D.. 2020-06-05. Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program. https://doi.org/10.1101/2020.06.04.134650

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