Activated STAT4 and a functional role for IL-12 in human Peyer's patches.
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.
Monteleone
Giovanni
G
Division of Infection, Inflammation, and Repair, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
Holloway
Judith
J
Salvati
Virginia M
VM
Pender
Sylvia L-F
SL
Fairclough
Peter D
PD
Croft
Nicholas
N
MacDonald
Thomas T
TT
D000293:Adolescent; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D004768:Enterotoxins / Q000494:pharmacology; D005260:Female; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D010581:Peyer's Patches / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D021122:Protein Subunits / Q000096:biosynthesis / Q000502:physiology; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000494:pharmacology; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; D004768:Enterotoxins; D007106:Immune Sera; D015848:Interleukin-5; D021122:Protein Subunits; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D018089:Superantigens; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D018664:Interleukin-12; D015847:Interleukin-4; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma