Department of Molecular Genetics, Osaka Medical Center for Cancer, Cardiovascular Diseases, Osaka, Osaka 537-8511, Japan
Interleukin-17A (IL17A), a characteristic cytokine produced by the T helper 17 cells (Th17 cells), can form either a homodimer or a heterodimer with IL17F. It is produced not only by Th17 cells, but also by cytotoxic CD8+<\/sup> T cells (Tc17 cells), γδ T cells, invariant natural killer T cells (iNKT cells), lymphoid tissue inducer cells (LTi cells), and other hematopoietic and non-hematopoietic cells. During development, these cells exhibit flexible or plastic features distinct from those of Th1 and Th2 cells. IL17A plays important roles in the pathogenesis of autoimmune diseases and in the host defenses against bacterial and fungal infections. Expression of IL17A and its related factors, as well as the infiltration of IL17A-producing cells into the tumor microenvironment, has been implicated in anti-tumor or pro-tumor effects in various cancers.
Th17 cells are a subset of helper T cells that have effector functions distinct from those of Th1 and Th2 cells. Early reports showed that stimulation with transforming growth factor β1 (TGFβ1) and IL6 is required to induce differentiation of IL17-producing CD4+ T cells (Th17 cells) from naïve CD4+ T cells (Korn et al., 2009). More recent reports have shown that Th17 cells can be categorized into two distinct subsets: conventional Th17 cells (Th17(β) cells, also called non-pathogenic Th17 cells), which differentiate in the presence of IL6 and TGFβ1, and Th17(23) cells (also called pathogenic Th17 cells), which differentiate in the presence of IL6, IL23 and IL1β without exogenous TGFβ1 (Ghoreschi et al., 2010; Basu et al., 2013; Kurebayashi et al., 2013). IL6 and IL1β can induce the expression of IL23 receptor in naïve CD4+ T cells in the absence of TGFβ1. Th17(β) cells express IL9, IL10, CCL20, and CXCR6 as well as IL17A and IL17F, whereas Th17(23) cells express IL22, CCL9 and CXCR3; relative to Th17(β) cells, Th17(23) cells make a greater contribution to pathogenesis in autoimmune diseases (Ghoreschi et al., 2010). Th17 cells stimulated with IL23, which is secreted by dendritic cells and macrophages following stimulation with Toll-like receptor (TLR) ligands, induce expression of TGFβ3, leading to the induction of pathogenic Th17(23) cells (Lee et al., 2012). These pathogenic Th17 cells are characterized by the expression of T-bet (TBX21, T-box protein 21), a master regulator of Th1-cell development, as well as RORγt. Compared with Th1 and Th2 differentiation, Th17-cell differentiation exhibits plastic or flexible features (Oestreich and Weinmann, 2012; Basu et al., 2013). TGFβ1 signaling induces the expression of both Foxp3 and RORγt in antigen-activated naïve CD4+ T cells and is involved in the differentiation of both iTreg and Th17 cells. Therefore, additional factors determine iTreg and Th17 polarization. Furthermore, iTreg and Th17 cells can transdifferentiate under specific conditions (Hoechst et al., 2011). The transition from Th17 cells to Th1 cells is also induced by IL23 and IL12 in a STAT4- and T-bet-dependent manner (Lee et al., 2009; Mukasa et al., 2010).
In addition to RORγt and the aforementioned cytokines, several transcriptional regulators positively regulate Th17 cell differentiation: signal transducer and activator of transcription 3 (STAT3), BATF (basic leucine zipper transcriptional factor, ATF-like), interferon regulatory factor 4 (IRF4), Runt-related transcriptional factor 1 (RUNX1), RORα and aryl hydrocarbon receptor (AHR, a nuclear receptor for a number of low-molecular weight chemicals such as the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ)) (Hirahara et al., 2010; Kurebayashi et al., 2013). Moreover, prostaglandin E2, ATP, and C-type lectin ligands act on antigen-presenting cells to facilitate Th17-cell differentiation. By contrast, IL4, interferon-γ (IFNγ), IL27, suppressor of cytokine signaling 3 (SOCS3), and STAT5 all suppress Th17-cell differentiation.
CD8+ T cells develop into Tc17 cells in the presence of TGFβ1 and either IL6 or IL21, similar to the requirements for Th17-cell development (Intlekofer et al., 2008). Tc17 cells are also characterized by the expression of RORγt, STAT3, RORα and IL23R. However, Tc17 cells do not express Granzyme B, and they exhibit impaired cytotoxic activity relative to conventional cytotoxic CD8+ T cells (Huber et al., 2009). A recent report suggested that TGFβ signaling is not required for in vivo differentiation of Tc17 cells (Dwivedi et al., 2012).
γδ T cells
Two distinct subsets of CD27+ or CD27- γδ T cells develop in the mouse fetal thymus: co-stimulation of TCR and CD27 induces CD27+ γδ T cells to express T-bet and produce IFNγ whereas the absence of TCR signaling (or weak signaling) promotes the development of IL17A-producing CD27- γδ T cells, a process controlled by RORγt and RUNX1 (Cua and Tato, 2010; Prinz et al., 2013). Because peripheral CD27- γδ T cells have permissive histone modification at loci involved in expression of not only Il17a but also Ifng, they can produce both IL17A and IFNγ upon stimulation with IL1β and IL23 (Schmolka et al., 2013). All innate IL17-producing lymphocytes, including γδ T cells, iNKT cells and LTi cells, express RORγt and develop in an IL6-independent manner (Cua and Tato, 2010).
iNKT cells are activated in response to glycolipid antigens presented by CD1d (Cua and Tato, 2010; Guo et al., 2012). IL17A-producing iNKT cells develop in the thymus, and express RORγt and IL23R. A recent report suggested that iNKT cells can be induced to produce IL17A in the presence of TGFβ1 and IL1β (Monteiro et al., 2013).
Innate lymphoid cells (ILCs), a family of RAG1/2-negative lymphoid cells, require the common cytokine receptor γ-chain (also known as IL2RG) and inhibitor of DNA binding 2 (ID2), a transcriptional repressor (Guo et al., 2012; Fuchs and Colonna, 2013; Spits et al., 2013). LTi cells, which like NK cells are prototypical ILCs, belong to the Group 3 ILCs (ILC3s), defined by the production of IL17A and/or IL22 (Spits et al., 2013). ILC3s require the expression of RORγt for their development, express IL23R and IL1R, and produce IL17A and/or IL22 upon stimulation with IL23 or IL1β.
A recent report shows that Trypanosoma crusi promotes IL17A production by B cells in human and mouse (Bermejo et al., 2013). T. crusi trans-sialidase mediates addition of sialyl residues onto CD45 expressed on B cells, resulting in induction of IL17A and F via BTK activation without the involvement of the transcriptional factors RORγt and AHR.
Although the details of the underlying signaling pathways and transcriptional factors are not known, cells other than lymphocytes, such as Paneth cells in the gut and CD11b+Gr1+ cells in the injured kidney also produce IL17A (Cua and Tato, 2010).
Norimitsu Inoue ; Takashi Akazawa
IL17A (interleukin 17A)
Atlas Genet Cytogenet Oncol Haematol. 2014-04-01
Online version: http://atlasgeneticsoncology.org/gene/40945/il17a-(interleukin-17a)
2011-01-01 IL17A (interleukin 17A) by Norimitsu Inoue,Takashi Akazawa