Cysteinyl leukotrienes mediate lymphokine killer activity induced by NKG2D and IL-15 in cytotoxic T cells during celiac disease

J Exp Med. 2015 Sep 21;212(10):1487-95. doi: 10.1084/jem.20150303. Epub 2015 Aug 24.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Arachidonate 5-Lipoxygenase / genetics
  • Arachidonate 5-Lipoxygenase / metabolism
  • Case-Control Studies
  • Celiac Disease / immunology*
  • Celiac Disease / physiopathology
  • Cells, Cultured
  • Cysteine / immunology
  • Cysteine / metabolism*
  • Female
  • Humans
  • Interleukin-15 / immunology*
  • Interleukin-15 / metabolism
  • Leukotrienes / immunology
  • Leukotrienes / metabolism*
  • Male
  • NK Cell Lectin-Like Receptor Subfamily K / immunology*
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Receptors, Leukotriene / genetics
  • Receptors, Leukotriene / metabolism
  • T-Lymphocytes, Cytotoxic / immunology*
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Up-Regulation


  • IL15 protein, human
  • Interleukin-15
  • KLRK1 protein, human
  • Leukotrienes
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Leukotriene
  • cysteinyl-leukotriene
  • Arachidonate 5-Lipoxygenase
  • ALOX5 protein, human
  • Cysteine
  • leukotriene D4 receptor