Activated STAT4 and a functional role for IL-12 in human Peyer's patches

Abstract

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-12R{beta}2, 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.

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Identifiers

ORCID for Judith Holloway: orcid.org/0000-0002-2268-3071

ORCID for Sylvia L.-F. Pender: orcid.org/0000-0001-6332-0333

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