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Immunity. 2016 Sep 20;45(3):610-625. doi: 10.1016/j.immuni.2016.07.018. Epub 2016 Sep 6.

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

Author information

1
INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France.
2
INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France; AP-HP, Department of Gastroenterology, Hôpital Européen Georges Pompidou, 75015 Paris, France.
3
Innate Immunity Unit, Institut Pasteur, 75015 Paris, France; INSERM U 668, 75015 Paris, France.
4
Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France; INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, 75015 Paris, France.
5
Université Paris Descartes-Sorbonne Paris Cité, Institut Necker-Enfants-Malades, INSERM UMR1151 and, Biological Hematology, AP-HP Necker-Enfants-Malades, 75015 Paris, France.
6
Paris-Descartes Bioinformatic Platform, 75015 Paris, France.
7
Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, 1649-028 Lisboa, Portugal.
8
Université Paris Descartes-Sorbonne Paris Cité, Institut Necker-Enfants-Malades, INSERM UMR1151 and, Biological Hematology, AP-HP Necker-Enfants-Malades, 75015 Paris, France; Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75010 Paris, France.
9
INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France. Electronic address: nadine.cerf-bensussan@inserm.fr.
10
INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France. Electronic address: bertrand.meresse@inserm.fr.

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.

PMID:
27612641
DOI:
10.1016/j.immuni.2016.07.018
[Indexed for MEDLINE]
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