Immunity
Volume 45, Issue 3, 20 September 2016, Pages 610-625
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Article
Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease

https://doi.org/10.1016/j.immuni.2016.07.018Get rights and content
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Highlights

  • Innate lymphocytes with T cell traits develop in the gut epithelium

  • They differentiate in situ from hematopoietic precursors, independently of Id2

  • Their differentiation requires sequential activation of NOTCH and IL-15 signals

  • JAK1 or STAT3 mutations can favor their clonal expansion in celiac disease

Summary

The nature of gut intraepithelial lymphocytes (IELs) lacking antigen receptors remains controversial. Herein we showed that, in humans and in mice, innate intestinal IELs expressing intracellular CD3 (iCD3+) differentiate along an Id2 transcription factor (TF)-independent pathway in response to TF NOTCH1, interleukin-15 (IL-15), and Granzyme B signals. In NOTCH1-activated human hematopoietic precursors, IL-15 induced Granzyme B, which cleaved NOTCH1 into a peptide lacking transcriptional activity. As a result, NOTCH1 target genes indispensable for T cell differentiation were silenced and precursors were reprogrammed into innate cells with T cell marks including intracellular CD3 and T cell rearrangements. In the intraepithelial lymphoma complicating celiac disease, iCD3+ innate IELs acquired gain-of-function mutations in Janus kinase 1 or Signal transducer and activator of transcription 3, which enhanced their response to IL-15. Overall we characterized gut T cell-like innate IELs, deciphered their pathway of differentiation and showed their malignant transformation in celiac disease.

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