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© Research
Publication : Immunity

Interleukin 15-Dependent T Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Immunity - 31 Aug 2016

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 JP, Cerf-Bensussan N, Meresse B

Link to Pubmed [PMID] – 27612641

Immunity 2016 Sept;45(3):610-25

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.

http://www.ncbi.nlm.nih.gov/pubmed/27612641