Interleukin-12 up-regulates perforin- and Fas-mediated lymphokine-activated killer activity by intestinal intraepithelial lymphocytes.
Human intraepithelial lymphocytes (IELs) comprise a unique compartment of memory T cell receptor (TCR)-alphabeta( +)CD8(+) T lymphocytes interspersed between intestinal epithelial cells. They develop potent lymphokine-activated killer (LAK) activity with interleukin (IL)-15, a cytokine that is found in excess in certain mucosal inflammatory states. IL-12, released by activated antigen-presenting cells, is known to potentiate perforin-induced cytotoxicity. This study evaluates the mechanism by which IL-12 up-regulates LAK activity. When IELs were stimulated with IL-15, the CD94(+) IEL subset expanded and carried out cytotoxic activity in redirected lysis against P815 cells as well as Fas ligand (FL)- and tumour necrosis factor (TNF)-alpha-mediated lysis of Jurkat and WEHI cells, respectively. IL-12 enhanced the perforin- and FL-, but not TNF-alpha-mediated events. In addition, the up-regulated killing of HT-29 cells by IL-12 was reduced by concanamycin (which targets perforin) and antibody neutralizing FL but not by anti-TNF-alpha antibody. Furthermore, IL-12 augmented IL-15-stimulated release of serine esterases as well as expression of perforin and FL by IELs, but not TNF-alpha. This study shows that LAK activity, carried out by the CD94(+) IELs, involves perforin, FL and TNF-alpha. IL-12 up-regulates the first two mechanisms of action, showing for the first time its effect on FL production and lytic activity.
Ebert
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UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA. jeydels@comcast.net
D015703:Antigens, CD / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology*; D019409:Interleukin-15 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology; D007583:Jejunum / Q000276:immunology; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000276:immunology*; D051920:NK Cell Lectin-Like Receptor Subfamily D; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D015703:Antigens, CD; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D019409:Interleukin-15; D007376:Interleukin-2; C497869:KLRD1 protein, human; D037181:Lectins, C-Type; D008024:Ligands; D008562:Membrane Glycoproteins; D051920:NK Cell Lectin-Like Receptor Subfamily D; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D018664:Interleukin-12