E-MTAB-4960 - INTERLEUKIN 15-DEPENDENT T CELL-LIKE INNATE INTRAEPITHELIAL LYMPHOCYTES DEVELOP IN THE INTESTINE AND TRANSFORM INTO LYMPHOMAS IN CELIAC DISEASE
Submitted on 19 July 2016, last updated on 23 November 2016, released on 23 November 2016
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.
transcription profiling by array, cell type comparison design
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 JP , Cerf-Bensussan N , Meresse B. Immunity 45(3):610-625 (2016), PMID:27612641