Interleukin 21 up‐regulates perforin‐mediated cytotoxic activity of human intra‐epithelial lymphocytes

Summary Human intra‐epithelial lymphocytes (IELs) are predominantly T‐cell receptor‐αβ + (TCR‐αβ + ) CD8 + CD45RO + memory T cells located between intestinal epithelial cells. They respond to a greater extent to stimulation with interleukin (IL)‐15 than to CD3/TCR triggering, suggesting that they react to the cytokine milieu in their local environment rather than to cognate antigen. A newly described member of the γc cytokine family, IL‐21, has potent antitumor effects. As IELs resemble lymphocytes infiltrating neoplastic lesions, their response to IL‐21 may be relevant in vivo . Here, IL‐21 was shown to increase perforin‐mediated cytotoxicity and serine esterase release by IELs. This IL‐21‐mediated up‐regulation occurred without changes in IEL survival or cell division. Interestingly, the effects of IL‐21 occurred without increased phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, STAT4, STAT5, extracellular signal‐regulated kinase (ERK), or p38. IL‐21 had no effect on Fas ligand (FL)‐ or tumour necrosis factor‐α (TNF‐α)‐mediated cytotoxicity, but it down‐regulated IL‐15‐stimulated expression of CD25 and CD94, indicating that it has both positive and negative actions. This functional profile is unique to human IELs, emphasizing that they are a distinct compartment of lymphocytes and that IL‐21 may promote their role in tumour immunosurveillance.