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

• Published in: Immunity (Cambridge, Mass.) Mass.), 2016-09, Vol.45 (3), p.610-625
• Main Authors: Ettersperger, Julien, Montcuquet, Nicolas, Malamut, Georgia, Guegan, Nicolas, Lopez-Lastra, Silvia, Gayraud, Ségolène, Reimann, Christian, Vidal, Elodie, Cagnard, Nicolas, Villarese, Patrick, Andre-Schmutz, Isabelle, Gomes Domingues, Rita, Godinho-Silva, Cristina, Veiga-Fernandes, Henrique, Lhermitte, Ludovic, Asnafi, Vahid, Macintyre, Elizabeth, Cellier, Christophe, Beldjord, Kheira, Di Santo, James P., Cerf-Bensussan, Nadine, Meresse, Bertrand
• Format: Article
• Language: English
• Subjects: Animals; Antigens; CD3 Complex - immunology; Celiac disease; Celiac Disease - immunology; Cell Differentiation - immunology; Cells, Cultured; Deoxyribonucleic acid; DNA; Flow cytometry; Granzymes - immunology; Humans; Inhibitor of Differentiation Protein 2 - immunology; Interleukin-15 - immunology; Intestines - immunology; Kinases; Lymphocyte Activation - immunology; Lymphocytes; Lymphoma - immunology; Mice; Mice, Inbred C57BL; Proteins; Receptor, Notch1 - immunology; Signal Transduction - immunology; Software; STAT3 Transcription Factor - immunology; Studies; T-Lymphocyte Subsets - immunology; Transcription factors; Transcription, Genetic - immunology
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.07.018

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. [Display omitted] •Innate lymphocytes with T cell traits develop in the gut epithelium•They differentiate in situ from hematopoietic precursors, independently of Id2•Their differentiation requires sequential activation of NOTCH and IL-15 signals•JAK1 or STAT3 mutations can favor their clonal expansion in celiac disease Ettersperger, Montcuquet et al. showed that innate lymphocytes with T cell traits were present in the gut epithelium. The latter cells differentiated independently of Id2 in response to NOTCH and IL-15 signals. They acquired gain-of-function mutations in JAK1 or STAT3, which favored their malignant transformation in celiac disease.