title: Interleukin 21 up-regulates perforin-mediated cytotoxic activity of  human intra-epithelial lymphocytes.
abstract: Human intra-epithelial lymphocytes (IELs) are predominantly T-cell receptor-alphabeta(+) (TCR-alphabeta(+)) 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 gammac 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-alpha (TNF-alpha)-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.
authors.affiliation: UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA. ebertec@umdnj.edu
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Ebert
mesh_terms: D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology; D053222:Fas Ligand Protein / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal; D019409:Interleukin-15 / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology*; D007583:Jejunum / Q000276:immunology; D054353:Perforin / Q000276:immunology*; D010766:Phosphorylation / Q000276:immunology; D050791:STAT Transcription Factors / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D053222:Fas Ligand Protein; D019409:Interleukin-15; D007378:Interleukins; D050791:STAT Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D000098546:Interleukin-21