Transcriptomics

Dataset Information

48

INTERLEUKIN 15-DEPENDENT T CELL-LIKE INNATE INTRAEPITHELIAL LYMPHOCYTES DEVELOP IN THE INTESTINE AND TRANSFORM INTO LYMPHOMAS IN CELIAC DISEASE


ABSTRACT: The nature of gut intraepithelial lymphocytes lacking antigen receptors remains controversial. Herein we showed that, in humans and in mice, innate intestinal intraepithelial lymphocytes expressing intracellular CD3 (iCD3+ innate IELs) 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. This pathway was operational in vivo in the mouse gut and led to the local differentiation of iCD3+ innate IELs from a bone marrow-derived precursor. In a subset of celiac patients, iCD3+ innate IELs with gain-of-function mutations in Janus kinase 1 or Signal transducer and activator of transcription 3 displayed enhanced response to IL-15 and acquired a selective advantage that favored clonal expansion and transformation into lymphoma. Overall we characterized gut T cell-like innate IELs, deciphered their pathway of differentiation, and showed their malignant transformation in celiac disease.

ORGANISM(S): Homo sapiens  

SUBMITTER: bertrand meresse   Nicolas Cagnard  

PROVIDER: E-MTAB-4960 | ArrayExpress | 2016-11-23

REPOSITORIES: ArrayExpress

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Publications


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 activ  ...[more]

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