Schematic representation of IL-15 lymphomagenic action leading to the emergence of EATL in CD. In active CD mucosa, IL-15, mainly produced by epithelial cells and dendritic cells (DCs), which present tissue transglutaminase (tTG)–deamidated gluten peptides to T cells in the context of HLA-DQ2 or HLA-DQ8 molecules, promotes the IEL cytotoxicity against epithelial cells by activating the perforin/granzyme system and favoring the interaction between the homodimeric NK activating receptor NFG2D and the major histocompatibility complex class I–related ligands (MIC), thus leading to enterocyte apoptosis. In addition, IL-15 inhibits IEL apoptosis, thus favoring the emergence of neoplastic IEL clonal proliferations, leading to the development of EATL. Activated gluten-reactive T helper cell type 1 cells (Th1) produce high levels of the proinflammatory cytokine IFN-γ, which contributes to the mucosal damage by further activating the cytotoxicity of IELs against enterocytes.