Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease.
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.
INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France.
Julien
J
Ettersperger
INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France.
Nicolas
N
Montcuquet
INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France; AP-HP, Department of Gastroenterology, Hôpital Européen Georges Pompidou, 75015 Paris, France.
Georgia
G
Malamut
INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France.
Nicolas
N
Guegan
Innate Immunity Unit, Institut Pasteur, 75015 Paris, France; INSERM U 668, 75015 Paris, France.
Silvia
S
Lopez-Lastra
INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France.
Ségolène
S
Gayraud
Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France; INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, 75015 Paris, France.
Christian
C
Reimann
Université Paris Descartes-Sorbonne Paris Cité, Institut Necker-Enfants-Malades, INSERM UMR1151 and, Biological Hematology, AP-HP Necker-Enfants-Malades, 75015 Paris, France.
Elodie
E
Vidal
Paris-Descartes Bioinformatic Platform, 75015 Paris, France.
Nicolas
N
Cagnard
Université Paris Descartes-Sorbonne Paris Cité, Institut Necker-Enfants-Malades, INSERM UMR1151 and, Biological Hematology, AP-HP Necker-Enfants-Malades, 75015 Paris, France.
Patrick
P
Villarese
Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France; INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, 75015 Paris, France.
Isabelle
I
Andre-Schmutz
Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, 1649-028 Lisboa, Portugal.
Rita
R
Gomes Domingues
Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, 1649-028 Lisboa, Portugal.
Cristina
C
Godinho-Silva
Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, 1649-028 Lisboa, Portugal.
Henrique
H
Veiga-Fernandes
Université Paris Descartes-Sorbonne Paris Cité, Institut Necker-Enfants-Malades, INSERM UMR1151 and, Biological Hematology, AP-HP Necker-Enfants-Malades, 75015 Paris, France.
Ludovic
L
Lhermitte
Université Paris Descartes-Sorbonne Paris Cité, Institut Necker-Enfants-Malades, INSERM UMR1151 and, Biological Hematology, AP-HP Necker-Enfants-Malades, 75015 Paris, France.
Vahid
V
Asnafi
Université Paris Descartes-Sorbonne Paris Cité, Institut Necker-Enfants-Malades, INSERM UMR1151 and, Biological Hematology, AP-HP Necker-Enfants-Malades, 75015 Paris, France.
Elizabeth
E
Macintyre
INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France; AP-HP, Department of Gastroenterology, Hôpital Européen Georges Pompidou, 75015 Paris, France.
Christophe
C
Cellier
Université Paris Descartes-Sorbonne Paris Cité, Institut Necker-Enfants-Malades, INSERM UMR1151 and, Biological Hematology, AP-HP Necker-Enfants-Malades, 75015 Paris, France; Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75010 Paris, France.
Kheira
K
Beldjord
Innate Immunity Unit, Institut Pasteur, 75015 Paris, France; INSERM U 668, 75015 Paris, France.
James P
JP
Di Santo
INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France. Electronic address: nadine.cerf-bensussan@inserm.fr.
Nadine
N
Cerf-Bensussan
INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, 75015 Paris, France. Electronic address: bertrand.meresse@inserm.fr.
Bertrand
B
Meresse
D000818:Animals; D017252:CD3 Complex / Q000276:immunology; D002446:Celiac Disease / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D053804:Granzymes / Q000276:immunology; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology*; D007422:Intestines / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008223:Lymphoma / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051881:Receptor, Notch1 / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology
D017252:CD3 Complex; D051797:Inhibitor of Differentiation Protein 2; D019409:Interleukin-15; D051881:Receptor, Notch1; D050796:STAT3 Transcription Factor; D053804:Granzymes