MicroRNA-146a controls Th1-cell differentiation of human CD4+ T lymphocytes by targeting PRKC[epsi]

T-cell functions must be tightly controlled to keep the balance between vital proinflammatory activity and detrimental overactivation. MicroRNA-146a (miR-146a) has been identified as a key negative regulator of T-cell responses in mice. Its role in human T cells and its relevance to human inflammatory disease, however, remains poorly defined. In this study, we have characterized miR-146a-driven pathways in primary human T cells. Our results identify miR-146a as a critical gatekeeper of Th1-cell differentiation processes acting via molecular mechanisms not uncovered so far. MiR-146a targets protein kinase C epsilon (PRKC[epsi]), which is part of a functional complex consisting of PRKC[epsi] and signal transducer and activator of transcription 4 (STAT4). Within this complex, PRKC[epsi] phosphorylates STAT4, which in turn is capable of promoting Th1-cell differentiation processes in human CD4+ T lymphocytes. In addition, we observed that T cells of sepsis patients had reduced levels of miR-146a and an increased PRKC[epsi] expression in the initial hyperinflammatory phase of the disease. Collectively, our results identify miR-146a as a potent inhibitor of Th1-cell differentiation in human T cells and suggest that dysregulation of miR-146a contributes to the pathogenesis of sepsis.