Activated STAT4 and a Functional Role for IL-12 in Human Peyer's Patches

• Published in: The Journal of immunology (1950) 2003-01, Vol.170 (1), p.300-307
• Main Authors: Monteleone, Giovanni, Holloway, Judith, Salvati, Virginia M, Pender, Sylvia L.-F, Fairclough, Peter D, Croft, Nicholas, MacDonald, Thomas T
• Format: Article
• Language: English
• Subjects: Adolescent; Cell Differentiation - immunology; Cells, Cultured; Child; Child, Preschool; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Enterotoxins - pharmacology; Female; Humans; Immune Sera - pharmacology; Interferon-gamma - biosynthesis; Interferon-gamma - metabolism; Interleukin-12 - biosynthesis; Interleukin-12 - immunology; Interleukin-12 - physiology; Interleukin-4 - metabolism; Interleukin-5 - metabolism; Intestinal Mucosa - cytology; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Lymphocyte Count; Lymphocytes - immunology; Lymphocytes - metabolism; Male; Peyer's Patches - cytology; Peyer's Patches - immunology; Peyer's Patches - metabolism; Protein Subunits - biosynthesis; Protein Subunits - physiology; Receptors, Interleukin - biosynthesis; Receptors, Interleukin-12; Staphylococcus aureus - immunology; STAT4 Transcription Factor; Superantigens - pharmacology; T-Box Domain Proteins; Th1 Cells - cytology; Th1 Cells - immunology; Trans-Activators - biosynthesis; Trans-Activators - metabolism; Trans-Activators - physiology; Transcription Factors - biosynthesis; Transcription Factors - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.170.1.300

T cells in the Peyer's patches (PP) of the human ileum are exposed to a myriad of dietary and bacterial Ags from the gut lumen. Recall proliferative responses to common dietary Ags are readily demonstrable by PP T cells from healthy individuals, and the cytokine response is dominated by IFN-gamma. Consistent with Th1 skewing, PP cells spontaneously secrete IL-12p70, and IL-12p40 protein can be visualized underneath the PP dome epithelium. In this study, we have analyzed IL-12 signaling in PP and investigated whether IL-12 plays a functional role. CD3+ T lymphocytes isolated from PP and adjacent ileal mucosa spontaneously secrete IFN-gamma with negligible IL-4 or IL-5. RNA transcripts for IL-12Rbeta2, the signaling component of the IL-12R, are present in purified CD4+ and CD8+ T PP lymphocytes. Active STAT4, a transcription factor essential for IL-12-mediated Th1 differentiation, is readily detectable in biopsies from PP and ileal mucosa and STAT4-DNA binding activity is demonstrable by EMSA. Nuclear proteins from CD3+ T PP lymphocytes contain STAT4 and T-bet, a transcription factor selectively expressed in Th1 cells. Stimulation of freshly isolated PP cells with staphylococcal enterotoxin B dramatically enhanced the production of IFN-gamma, an effect which was largely inhibited by neutralizing anti-IL-12 Ab. These data show that IL-12 in human PP is likely to be responsible for the Th1-dominated cytokine response of the human mucosal immune system.