Interleukin‐12 up‐regulates perforin‐ and Fas‐mediated lymphokine‐activated killer activity by intestinal intraepithelial lymphocytes

• Published in: Clinical and experimental immunology Vol. 138; no. 2; pp. 259 - 265
• Main Author: EBERT, E. C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.11.2004; Blackwell; Blackwell Science Inc
• Subjects: Antigens, CD - immunology; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; cytotoxicity; Cytotoxicity, Immunologic - immunology; Epithelial Cells - immunology; Fas; Fas Ligand Protein; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunopathology; Interleukin-12 - immunology; Interleukin-15 - immunology; Interleukin-2 - immunology; Intestinal Mucosa - immunology; intraepithelial lymphocytes; Jejunum - immunology; Killer Cells, Lymphokine-Activated - immunology; Lectins, C-Type - immunology; Ligands; Medical sciences; Membrane Glycoproteins - immunology; NK Cell Lectin-Like Receptor Subfamily D; Original; Perforin; Pore Forming Cytotoxic Proteins; T-Lymphocytes, Cytotoxic - immunology; TNF; Tumor Necrosis Factor-alpha - immunology; Up-Regulation - immunology; Immunopathology; Cytolysin; Digestive system; cytotoxicity Fas intraepithelial lymphocytes perforin TNF; Cytokine; Gut; Activity; Interleukin 12; Epithelium; Regulation(control); Immunology; LAK cell; Fas Antigen; Perforin; Lymphocyte
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2004.02614.x

SUMMARY Human intraepithelial lymphocytes (IELs) comprise a unique compartment of memory T cell receptor (TCR)‐αβ +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)‐α‐mediated lysis of Jurkat and WEHI cells, respectively. IL‐12 enhanced the perforin‐ and FL‐, but not TNF‐α‐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‐α 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‐α. This study shows that LAK activity, carried out by the CD94+ IELs, involves perforin, FL and TNF‐α. IL‐12 up‐regulates the first two mechanisms of action, showing for the first time its effect on FL production and lytic activity.