Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Immunity (Cambridge, Mass.), 2016-09, Vol.45 (3), p.610-625

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.