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Activated STAT4 and a Functional Role for IL-12 in Human Peyer’s Patches¹

Giovanni Monteleone^*, Judith Holloway^*, Virginia M. Salvati, Sylvia L.-F. Pender^*, Peter D. Fairclough, Nicholas Croft and Thomas T. MacDonald^2,*

^* Division of Infection, Inflammation, and Repair, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom; Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy; and Department of Adult and Paediatric Gastroenterology, St. Bartholomew’s and Royal London School of Medicine, St. Bartholomew’s Hospital, London, United Kingdom

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-. 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- with negligible IL-4 or IL-5. RNA transcripts for IL-12R2, 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-, 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.

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