Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease.
Immunity
; 45(3): 610-625, 2016 09 20.
Article
en En
| MEDLINE
| ID: mdl-27612641
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Enfermedad Celíaca
/
Subgrupos de Linfocitos T
/
Interleucina-15
/
Intestinos
/
Linfoma
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Immunity
Asunto de la revista:
ALERGIA E IMUNOLOGIA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Francia