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 ind...

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Published in:The Journal of clinical investigation 2010-06, Vol.120 (6), p.2131-2143
Main Authors: Malamut, Georgia, El Machhour, Raja, Montcuquet, Nicolas, Martin-Lannerée, Séverine, Dusanter-Fourt, Isabelle, Verkarre, Virginie, Mention, Jean-Jacques, Rahmi, Gabriel, Kiyono, Hiroshi, Butz, Eric A, Brousse, Nicole, Cellier, Christophe, Cerf-Bensussan, Nadine, Meresse, Bertrand
Format: Article
Language:English
Subjects:
Adult
Apoptosis
Apoptosis - drug effects
Apoptosis - immunology
Biomedical research
Care and treatment
Celiac disease
Celiac Disease - complications
Celiac Disease - immunology
Celiac Disease - metabolism
Cytokines
Cytokines - immunology
Cytokines - metabolism
Cytokines - pharmacology
Development and progression
Enterocytes - immunology
Enterocytes - metabolism
Gluten
Health aspects
Humans
Inflammation
Inflammation - complications
Inflammation - immunology
Inflammation - metabolism
Interleukin-15
Interleukin-15 - immunology
Interleukin-15 - metabolism
Interleukin-15 - pharmacology
Intestine, Small - immunology
Intestine, Small - metabolism
Intestines - immunology
Intestines - metabolism
Janus Kinase 3 - immunology
Janus Kinase 3 - metabolism
Leukemia - complications
Leukemia - immunology
Leukemia - metabolism
Lymphocytes
Lymphocytes - immunology
Lymphocytes - metabolism
Lymphoma
Medical prognosis
Non-Hodgkin's lymphomas
Phosphorylation
Properties
Protein Binding - immunology
Signal Transduction - drug effects
Signal Transduction - immunology
STAT3 Transcription Factor - immunology
STAT3 Transcription Factor - metabolism
STAT3 Transcription Factor - pharmacology
T cell receptors
T cells
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI41344