Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease.
Ettersperger J,Montcuquet N,Malamut G,Guegan N,Lopez-Lastra S,Gayraud S,Reimann C,Vidal E,Cagnard N,Villarese P,Andre-Schmutz I,Gomes Domingues R,Godinho-Silva C,Veiga-Fernandes H,Lhermitte L,Asnafi V,Macintyre E,Cellier C,Beldjord K,Di Santo J,Cerf-Bensussan N,Meresse B
Source :
Immunity
2016 Sep 6
Pmid / DOI:
27612641
Abstract
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.Copyright © 2016 Elsevier Inc. All rights reserved.