title: IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis.
abstract: 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.
authors.affiliation: INSERM U989, Paris, France.
authors.forename: Georgia
authors.initials: G
authors.lastname: Malamut
authors.forename: Raja
authors.initials: R
authors.lastname: El Machhour
authors.forename: Nicolas
authors.initials: N
authors.lastname: Montcuquet
authors.forename: Séverine
authors.initials: S
authors.lastname: Martin-Lannerée
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dusanter-Fourt
authors.forename: Virginie
authors.initials: V
authors.lastname: Verkarre
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Mention
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rahmi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyono
authors.forename: Eric A
authors.initials: EA
authors.lastname: Butz
authors.forename: Nicole
authors.initials: N
authors.lastname: Brousse
authors.forename: Christophe
authors.initials: C
authors.lastname: Cellier
authors.forename: Nadine
authors.initials: N
authors.lastname: Cerf-Bensussan
authors.forename: Bertrand
authors.initials: B
authors.lastname: Meresse
mesh_terms: 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
chemical_list: D016207:Cytokines; D019409:Interleukin-15; D050796:STAT3 Transcription Factor; D053616:Janus Kinase 3