Regulation of IL-17 production in human lymphocytes

Abstract

The discovery of a new lineage of helper T cells that selectively produces interleukin (IL)-17 has provided exciting new insights into immunoregulation, host defense and the pathogenesis of autoimmune diseases. Although the factors that promote murine Th17 differentiation have been intensively examined, there has been much less information on the regulation of this cytokine in human T cells. IL-17 is readily produced by human memory T cells, which we now know exhibit distinct patterns of chemokine receptor expression and may differentiate in response to selective pathogens. Recently it has been shown that IL-1, IL-6 and IL-23 are important in driving human Th17 differentiation. However, TGFbeta-1 which is important for the differentiation of murine Th17 cells and inducible regulatory T cells (iTregs), is reportedly not required and even inhibits for human Th17 differentiation. In addition, human Th17 cells also produce other proinflammatory cytokines. Further characterization of the transcription regulation of human IL-17 expression, and the epigenetic regulation of human Il17 locus should improve our understanding the lineage commitment of human Th17 cells. Targeting the production and action of this cytokine is also likely to be beneficial therapeutically for autoinflammatory and autoimmune diseases.

Divergence and similarity of mouse and human Th17 differentiation.

Upon activation by antigen-presenting cells, in the presence of IL-6, TGFβ−1 and IL-21, mouse naïve CD4+ T cells differentiate to Th17 cells, which produce IL-17A, IL-17F, IL-21, IL-22 and TNFα. Transcription factors including RORγt, Stat3, and IRF4 are involved in regulating this process. In human naïve CD4+ T cells, cytokines IL-6, IL-1 and IL-23 promote Th17 differentiation but surprisingly, TGFβ−1 is not involved. The transcription factors NFAT (from TCR stimulation), RORγt have been implicated in regulating human IL-17 expression, although it is also likely that Stat3 is also important. In addition to IL-17A, IL-17F, IL-22 and TNF, human Th17 cells also produce IL-26. Cytokines such as IL-4 and IFN-γ negatively regulate both mouse and human IL-17 production. IL-2 signaling through Stat5 inhibits murine Th17 differentiation but it appears to have distinct temporal effects, especially in regulating human Th17 development (denoted by *). That is, at early points in differentiation, IL-17 production is inhibited. Later on IL-2 appears to expand IL-17 producing effector/memory cells. Retinoic acid (RA) is another negative regulator for IL-17 expression in murine T cells but this effect has not been confirmed in human T cells. Although IL-27 negatively regulates murine Th17 differentiation, it is uncertain if this cytokine directly inhibits IL-17 production in human T cells. Human Th17 cells express chemokine receptors CCR6 and CCR4 whereas cells that produce IL-17 and IFN-γ express CCR6 and CXCR3. Similar chemokine receptor expression pattern has not been characterized in mouse Th17 cells.