IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis.
Enteropathy-associated T cell lymphoma is a severe complication of celiac disease (CD). One mechanism suggested to underlie its development is chronic exposure of intraepithelial lymphocytes (IELs) to potent antiapoptotic signals initiated by IL-15, a cytokine overexpressed in the enterocytes of individuals with CD. However, the signaling pathway by which IL-15 transmits these antiapoptotic signals has not been firmly established. Here we show that the survival signals delivered by IL-15 to freshly isolated human IELs and to human IEL cell lines derived from CD patients with type II refractory CD (RCDII) - a clinicopathological entity considered an intermediary step between CD and enteropathy-associated T cell lymphoma - depend on the antiapoptotic factors Bcl-2 and/or Bcl-xL. The signals also required IL-15Rbeta, Jak3, and STAT5, but were independent of PI3K, ERK, and STAT3. Consistent with these data, IELs from patients with active CD and RCDII contained increased amounts of Bcl-xL, phospho-Jak3, and phospho-STAT5. Furthermore, incubation of patient duodenal biopsies with a fully humanized human IL-15-specific Ab effectively blocked Jak3 and STAT5 phosphorylation. In addition, treatment with this Ab induced IEL apoptosis and wiped out the massive IEL accumulation in mice overexpressing human IL-15 in their gut epithelium. Together, our results delineate the IL-15-driven survival pathway in human IELs and demonstrate that IL-15 and its downstream effectors are meaningful therapeutic targets in RCDII.
Malamut
Georgia
G
INSERM U989, Paris, France.
El Machhour
Raja
R
Montcuquet
Nicolas
N
Martin-Lannerée
Séverine
S
Dusanter-Fourt
Isabelle
I
Verkarre
Virginie
V
Mention
Jean-Jacques
JJ
Rahmi
Gabriel
G
Kiyono
Hiroshi
H
Butz
Eric A
EA
Brousse
Nicole
N
Cellier
Christophe
C
Cerf-Bensussan
Nadine
N
Meresse
Bertrand
B
D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002446:Celiac Disease / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D020895:Enterocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000276:immunology / Q000378:metabolism; D007422:Intestines / Q000276:immunology; D053616:Janus Kinase 3 / Q000276:immunology / Q000378:metabolism; D007938:Leukemia / Q000150:complications / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D019409:Interleukin-15; D050796:STAT3 Transcription Factor; D053616:Janus Kinase 3