Abstract

Abstract TCRαβ+ CD8α+ CD8β− intraepithelial lymphocytes (CD8αα IEL) differentiate from thymic IEL precursors (IELp) and contribute to gut homeostasis. However, their development remains poorly understood. Here we show that the zinc finger transcription factor LRF, encoded by Zbtb7a, is highly expressed in both CD8αα+ IELs and in IELp and serves in a cell-intrinsic manner to promote IEL differentiation. Mice genetically deficient for LRF (Cd4-Cre Zbtb7afl/fl) lack CD8αα+ IELs, contrasting with largely conserved numbers of conventional CD8αβ+ T cells in the thymus and the secondary lymphoid organs. Unlike their wild-type counterparts, LRF-deficient IELp failed to prevent colitis caused by adoptive transfer of CD4+ T cells in T cell-deficient mice. LRF disruption affects neither the development of thymic IELp, nor their in vitro expansion or differentiation in response to IL-15. However, Cd4-Cre Zbtb7afl/fl mice accumulate CD8αα+ T cells in the spleen, unlike wild-type controls, suggesting impaired migration of IELp to the gut. Single-cell RNA sequencing found LRF necessary for the expression of genes characteristic of the most mature IELp, including Itgb7, encoding the β7 subunit of α4β7. Chromatin immunoprecipitation and gene regulatory network analyses both defined Itgb7 as an LRF target. Our study identifies LRF as an essential transcriptional regulator of IELp maturation in the thymus and subsequent migration to the intestinal epithelium.

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