title: Cysteinyl leukotrienes mediate lymphokine killer activity induced by NKG2D and IL-15 in cytotoxic T cells during celiac disease.
abstract: Eicosanoids are inflammatory mediators that play a key but incompletely understood role in linking the innate and adaptive immune systems. Here, we show that cytotoxic effector T cells (CTLs) are capable of both producing and responding to cysteinyl leukotrienes (CystLTs), allowing for the killing of target cells in a T cell receptor-independent manner. This process is dependent on the natural killer receptor NKG2D and exposure to IL-15, a cytokine induced in distressed tissues. IL-15 and NKG2D signaling drives the up-regulation of key enzymes implicated in the synthesis of CystLTs, as well as the expression of CystLT receptors, suggesting a positive feedback loop. Finally, although the CystLT pathway has been previously linked to various allergic disorders, we provide unexpected evidence for its involvement in the pathogenesis of celiac disease (CD), a T helper 1 cell-mediated enteropathy induced by gluten. These findings provide new insights into the cytolytic signaling pathway of NKG2D and the pathogenesis of organ-specific immune disorders. Furthermore, they suggest that the blockade of CystLT receptors may represent a potent therapeutic target for CD or potentially other autoimmune disorders in which NKG2D has been implicated.
authors: Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637.
authors: Fangming
authors: F
authors: Tang
authors: Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637.
authors: Benjamin
authors: B
authors: Sally
authors: Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637.
authors: Kathryn
authors: K
authors: Lesko
authors: Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 European Laboratory for the Investigation of Food-Induced Disorders (ELFID), Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, 80138 Naples, Italy.
authors: Valentina
authors: V
authors: Discepolo
authors: Sainte-Justine Hospital Research Center, Department of Microbiology, Infectiology, and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada.
authors: Valerie
authors: V
authors: Abadie
authors: Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637.
authors: Cezary
authors: C
authors: Ciszewski
authors: Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637.
authors: Carol
authors: C
authors: Semrad
authors: Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637.
authors: Stefano
authors: S
authors: Guandalini
authors: Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637.
authors: Sonia S
authors: SS
authors: Kupfer
authors: Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 Department of Medicine, University of Chicago Celiac Disease Center, and Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL 60637 bjabri@bsd.uchicago.edu.
authors: Bana
authors: B
authors: Jabri
mesh_terms: D000328:Adult; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002446:Celiac Disease / Q000276:immunology* / Q000503:physiopathology; D002478:Cells, Cultured; D003545:Cysteine / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology* / Q000378:metabolism; D015289:Leukotrienes / Q000276:immunology / Q000378:metabolism*; D008297:Male; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology* / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C569274:IL15 protein, human; D019409:Interleukin-15; C527085:KLRK1 protein, human; D015289:Leukotrienes; D055655:NK Cell Lectin-Like Receptor Subfamily K; D018077:Receptors, Leukotriene; C112381:cysteinyl-leukotriene; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human; D003545:Cysteine; C083169:leukotriene D4 receptor