As described above, Th17 can co-secrete IFN- (Annunziato et al., 2007; Lee et al., 2009; Cosmi et al., 2011; Hirota et al., 2011) or co-express FOXP3 (Ayyoub et al., 2009; Beriou et al., 2009; Miyara et al., 2009; Voo et al., 2009; Kryczek et al., 2011; Ye et al., 2011), indicating the existence of multiple subsets of Th17 cells with functional specialization (Figure ?(Figure11). Open in a separate window Figure 1 The protective and pathogenic functions of Th17 cells. et al., 2012). They constitutively co-express CCR4 and CCR6, but not CXCR3 (Acosta-Rodriguez et al., 2007b), and are derived from CD161+ precursors (Cosmi et al., 2008). The effects of Th17 IDH-305 cells on other cells have recently been highlighted in many reviews (Annunziato and Romagnani, 2011; Gaffen, 2011; Gaffen et al., 2011; Ghoreschi et al., 2011; Milner, 2011; Pappu et al., 2011; Wilke et al., 2011). Th17 cells initially developed a reputation as a destructive element in several diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (IBD). In animal models this reputation, came from evidence that the lack of IL-17-producing cells ameliorates experimental autoimmune encephalitis (EAE) and collagen induced arthritis (CIA; Cua et al., 2003). In humans, the reputation was due to correlative data documenting an increase in IL-17-producing cells, particularly at sites of tissue inflammation (Wilke et al., 2011). However, these original conclusions were over-simplified and as discussed below in some diseases Th17 cells clearly have a protective role. The Role of Th17 Cells in Primary Immunodeficiencies Much of what we know about human Th17 cells comes from the study of a rare primary immunodeficiency called Hyperimmunoglobulin E (Jobs, syndrome). This disease is caused by mutations in Rabbit Polyclonal to CHST6 (Holland et al., 2007) but the underlying cellular basis for the characteristic phenotype of severe pneumonias, mucocutaneous candidiasis, and abscesses (Buckley et al., 1972; Grimbacher et al., 1999) remained unknown until several groups found that these patients lack Th17 cells in their peripheral blood (de Beaucoudrey et al., 2008; Ma et al., 2008; Milner et al., 2008; Renner et al., 2008). In addition, na?ve Th cells from Jobs syndrome patients have low levels of RORC2 expression and cannot be differentiated into Th17 cells (de Beaucoudrey et al., 2008; Ma et al., 2008; Milner et al., 2008; Renner et al., 2008). One complication when interpreting data from Jobs syndrome patients is that STAT3 is activated downstream IDH-305 of other cytokines, making it difficult to attribute a clinical phenotype to one pathway. Recently, other immunodeficiencies have been described which involve more specific defects in the IL-17 pathway. For example, two patients with chronic mucocutaneous candidiasis (CMC) disease, characterized by chronic or persistent infection with and infection (Glocker et al., 2009) and have low numbers of Th17 cells in their peripheral blood. Together, these data have led to the hypothesis that in humans Th17 cells have an essential role in protective immunity the specific pathogens and with antigen specific stimulation by and (Zielinski et al., 2012). Th17 cells have an intriguing close developmental link with FOXP3+CD4+ regulatory T cells (Tregs). FOXP3 and RORC2 can directly interact via a DNA-independent mechanism, and during Th17 cell development FOXP3 is transiently expressed (Zhou et al., 2008). Moreover, upon activation fully differentiated human Th17 cells preferentially express FOXP3 in comparison to Th1 cells (McMurchy and Levings, unpublished data). Indeed there is increasing evidence for the existence of cells that co-express IL-17 and FOXP3 (Ayyoub et al., 2009; Beriou et al., 2009; Miyara et al., 2009; Voo et al., 2009; Kryczek et al., 2011; Ye et al., 2011). Immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome (IPEX) is a triad of autoimmune syndromes including enteropathy, type 1 diabetes, and hyper-IgE (McMurchy et al., 2010), resulting from mutations in polarized Th17 cells, especially if the monolayer is pre-treated with IL-17 or IL-22 (Kebir et al., 2007). These data led to the hypothesis that in MS Th17 cells weaken the blood-brain barrier and enable the migration of immune cells into the normally immune privileged sites within the central nervous IDH-305 system. If this is the case, then Th17 cells may have more of a facilitative than directly pathogenic role in the nervous system, distinct from their clear role in the positive feedback loop of inflammation in psoriasis and RA. Recruitment has begun for a phase II clinical trials of Secukinumab in patients with relapsing-remitting MS. This trial will provide significant insight into the question of whether IL-17 blockade in MS can induce a clinically relevant protective function. Type 1 diabetes (T1D) is characterized by autoimmune destruction of pancreatic islet cells resulting in the loss of insulin production. Murine studies have yielded conflicting results on the.