Expression of IL‐10 in Th memory lymphocytes is conditional on IL‐12 or IL‐4, unless the IL‐10 gene is imprinted by GATA‐3

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Abstract
In Th1 and Th2 memory lymphocytes, the genes for the cytokines interleukin (IL)‐4 and interferon‐γ (IFN‐γ) are imprinted for expression upon restimulation. This cytokine memory is based on expression of the transcription factors T‐bet for IFN‐γ, and GATA‐3 for IL‐4, and epigenetic modification of the cytokine genes. In Th2 cells, expression of the cytokine IL‐10 is also induced by GATA‐3. Here, we show that this induction is initially not accompanied by epigenetic modification of the IL‐10 gene. Only after repeated restimulation of a memory Th2 cell in the presence of IL‐4, extensive histone acetylation of the IL‐10 gene is detectable. This epigenetic imprinting correlates with the development of a memory for IL‐10 in repeatedly restimulated Th2 cells. In Th1 cells, IL‐10 expression is induced by IL‐12, but the IL‐10 gene lacks detectable histone acetylation. Accordingly, IL‐10 expression in restimulated memory Th1 cells remains conditional on the presence of IL‐12. This finding defines a potential anti‐inflammatory role for IL‐12 in Th1 recall responses. While in primary Th1 responses IL‐12 is required to induce expression of the pro‐inflammatory cytokine IFN‐γ, in secondary Th1 responses IFN‐γ re‐expression is independent of IL‐12, which still is able to induce expression of the anti‐inflammatory cytokine IL‐10.