in rare cases , a mutation in an essential gene can disrupt immune homeostasis , leading to clinical immunodeficiency . more commonly , when individuals with a genetic predisposition are exposed to environmental triggers , a failure of immune homeostasis can lead to autoimmunity . in this review , we will discuss how parallel studies of immunodeficiencies and autoimmune diseases have advanced our knowledge of a cd4 t cell lineage first characterized by production of il-17a , th17 cells . 2005 ) and , as for other cd4 t cell lineages , their development , is controlled by a combination of cytokines which initiate a program of transcription factor expression and epigenetic re - modeling ( van der gast et al . , 2011 ) . in humans , the cytokines which instruct th17 cell lineage development likely include il-6 , il-21 , il-23 , and il-1 ( acosta - rodriguez et al . , 2007a ; chen et al . , 2007 ; evans et al . , 2007 ; wilson et al . , 2007 ; liu and rohowsky - kochan , 2008 ) , with a potential synergistic role for tgf- ( manel et al . , 2008 ; , 2008 ; yang et al . , 2008a ) via its ability to suppress th1 cell lineage commitment ( santarlasci et al . , 2009 ) . cytokine - driven activation of the signal transducer and activator of transcription ( stat ) 3 pathway is an essential step in th17 cell differentiation ( holland et al . , 2007 ; yang et al . ultimately leading to expression of their lineage - defining transcription factor : retinoid orphan receptor ( ror)c2 ( acosta - rodriguez et al . , 2007a ; annunziato et al . , 2007 ; wilson et al . , 2007 although the il-17 cytokine family includes six members ( kolls and linden , 2004 ) , th17 cells are thought to only produce il-17a and il-17f , which are 55% identical ( kolls and linden , 2004 ) . il-17a can combine with il-17f to form a heterodimer and both can form homodimers ( wright et al . , 2007 ) . in addition to il-17a and il-17f , th17 cells secrete other signature cytokines including il-21 and il-22 ( bending et al . , 2011 ) . they have also been reported to produce ifn- ( annunziato et al . , 2007 ) , il-4 ( cosmi et al . , 2010 ) , il-10 ( mcgeachy et al . , 2007 ) , il-9 ( beriou et al . , 2010 ) , il-26 , cxcl8 , and ccl20 ( boniface et al . , 2008 ) . they are poor producers of il-2 , which may result in their poor proliferative potential in vitro ( santarlasci et al . , 2012 ) . they constitutively co - express ccr4 and ccr6 , but not cxcr3 ( acosta - rodriguez et al . , 2007b ) , and the effects of th17 cells on other cells have recently been highlighted in many reviews ( annunziato and romagnani , 2011 ; gaffen , 2011 ; gaffen et al . 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 . 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 . much of what we know about human th17 cells comes from the study of a rare primary immunodeficiency called hyperimmunoglobulin e ( job s , syndrome ) . this disease is caused by mutations in stat3 ( holland et al . , 2007 ) but the underlying cellular basis for the characteristic phenotype of severe pneumonias , mucocutaneous candidiasis , and staphylococcus aureus 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 ; in addition , nave th cells from job s syndrome patients have low levels of rorc2 expression and can not be differentiated into th17 cells in vitro ( de beaucoudrey et al . , 2008 ; ma et al . , 2008 ; milner et al . , 2008 one complication when interpreting data from job s syndrome patients is that stat3 is activated downstream 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 candida albicans and s. aureus , were found to have an il-17ra autosomal recessive deficiency or an il-17f autosomal dominant deficiency ( puel et al . , 2011 ) . in addition , patients with a deficiency in the intracellular adaptor molecule card9 , which is essential for dectin-1 signaling , also suffer from systemic candidiasis 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 c. albicans and s. aureus . in accordance with this conclusion , sallusto et al . have characterized different subsets of human th17 cells that can be differentiated in vitro with antigen specific stimulation by c. albicans and s. aureus ( zielinski et al . , 2012 ) . th17 cells have an intriguing close developmental link with foxp3cd4 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 ; 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 foxp3 . the cellular basis for this disease has been attributed to treg dysfunction ( bacchetta et al . , 2006 ; dhennezel et al . , 2009 ) , but recently bacchetta et al . investigated whether part of the cellular defect in ipex patients may not only relate to treg dysfunction , but also to changes in th17 cells . indeed ipex patients possessed an increased frequency of cells with a surface profile characteristic of th17 cells ( cd4ccr6cd161 ) , expressing rorc2 , and producing il-17 ( passerini et al . , 2011 ) . interestingly , in patients with point mutations that do not abrogate foxp3 expression , there was an increased frequency of foxp3 cells within the cd161 th17 cell gate . these data suggest that dysfunctional tregs may preferentially differentiate into th17 cells and that an expansion of this subset may underlie some of the clinical phenotype of ipex . an alternative interpretation is that the th17 cells in ipex patients are highly activated and that in this case foxp3 expression is a consequence of t cell activation and not treg lineage commitment ( ziegler , 2006 ) . regardless , in this immunodeficiency there is strong correlative evidence that th17 cells may have a detrimental pro - inflammatory effect . the first recognition of the importance of th17 cells came from studies of eae . the notion of eae as a th1-mediated disease was challenged when mice deficient in the p40 subunit of il-12 were found to be resistant to eae whereas mice deficient in the p35 subunit were actually more susceptible to disease ( becher et al . , 2002 ) . ( 2003 ) solved this paradox by using genetically deficient mice to show that il-23p19 and il-12p40 , but not il-12p35 , were essential for eae development . il-23 , which shares the il-12p40 subunit with il-12 , was subsequently found to stabilize th17 cells , and these cells were found to be the main contributing factor in eae ( langrish et al . , 2005 ) . below we discuss the evidence for a pro - inflammatory role in autoimmunity and describe attempts to target this axis therapeutically . psoriasis is an auto - inflammatory skin disease characterized by recurrent demarcated red and scaly skin plaques . these plaques include infiltrating t cells ( mainly th cells ) and dendritic cells in the dermis as well as cytotoxic t cells and neutrophil in the epidermis ( lowes et al . , 2007 ) . the resulting inflammatory process results in rapid keratinocyte proliferation , abnormal keratinocyte differentiation , and angiogenesis ( lowes et al . , 2007 ) . initially , increased levels of ifn- , tnf- , and il-12 in the serum and lesions of psoriasis patients labeled this as a th1-mediated disease ( di cesare et al . , 2009 ) . however , rorc , il-1 , il-6 , and il-23 are also increased in psoriatic skin lesions ( di cesare et al . , 2009 ) leading to the possibility that th17 and th1 act in synergy to produce psoriatic inflammation . th17 cells are thought to be recruited to the skin by expression of ccl20 , the ligand for ccr6 , then locally stabilized by il-1 and il-23 . since both il-17 and ifn- cause keratinocytes and antigen presenting cells ( apcs ) to produce more il-1 , il-23 , and ccl20 , a positive feedback loop causing keratinocyte proliferation is established ( kryczek et al . , 2008 ; zaba et al . , several monoclonal antibodies targeting tnf- and the p40 subunit shared by il-12 and il-23 ( ustekinumab ) have been approved for clinical use in psoriasis . since il-17 can act synergistically with tnf- to induce keratinocytes to express inflammatory proteins ( chiricozzi et al . , 2011 ) , it is possible that anti - tnf- acts in part by inhibiting th17 cell - driven inflammation . targeting il-17 alone with secukinumab ( ain457 ) or ixekizumab , both fully human neutralizing antibodies to il-17a , is also effective in psoriasis ( hueber et al . , 2010 ; leonardi et al . , 2012 ) , confirming that this is likely a major pathogenic cytokine in this skin disease . since th17 cells are not the sole producers of il-17 [ other possible sources of this cytokine in psoriatic plaques include  t cells ( cai et al . , 2011 ) , mast cells ( lin et al . , 2011 ) , neutrophils ( lin et al . , 2011 ) , and tregs ( bovenschen et al . , 2011 ) ] , whether or not th17 cells are the major source of this cytokine in skin remains to be determined . another disease with strong links to th17 cells is ra , a chronic autoimmune disease that leads to joint destruction . t cells infiltrating the synovial fluid of ra patients produce high amounts of il-17a , il-1 , and il-6 ( cascao et al . , 2010 ) , especially during early disease and pre - treatment ( chabaud et al . , 1999 ; notably , the levels of il-17 in the synovium correlate with joint damage , whereas those of ifn- correlate with protection ( kirkham et al . , 2006 ) . recent evidence supports a role for il-17f as well as il-17a in ra , with the two related cytokines acting in synergy to induce other pro - inflammatory cytokines and chemokines in synoviocytes , myeloid cells , and synovial fibroblasts ( lundy et al . hence , analogous to the process in psoriasis , a positive pro - inflammatory feedback loop encourages more th17 differentiation and maintenance in the joint ( reviewed in sarkar and fox , 2010 ) . direct clinical evidence for the role of il-17 in ra comes from recent clinical trials which found that secukinumab and another anti - il-17a therapeutic known as ly2439821 significantly benefit these patients ( genovese et al . , 2010 ; morrison et al . , multiple sclerosis is a neurological disease that results from auto - inflammatory damage to the myelin sheaths surrounding nerves in the brain and spinal cord . this disease has historically been associated with the discovery of th17 cells since , as discussed above , they have a major pathogenic role in eae ( bettelli et al . , 2008 ; dong , 2008 ; dubin and kolls , 2008 ; weaver and hatton , 2009 ) . ms patients have increased il-17 mrna in their blood as well as cerebrospinal fluid ( matusevicius et al . , 1999 ) , and expression of mirna326 in their peripheral blood mononuclear cells promotes th17 cell differentiation and correlates with disease severity ( du et al . , 2009 ) . blood - brain barrier endothelial cells layers are more permeable to in vitro 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 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 role of th17 in the nod mouse model of t1d ( vukkadapu et al . , 2005 ; jain et al . , 2008 ; emamaullee et al . , 2009 ; van den brandt et al . , ; joseph et al . , 2012 ) , including a potential ability to convert into th1 cells in vivo ( bending et al . , however , more recent data suggest some of this apparent plasticity could be related to the study of in vitro polarized th17 cells , which are not sufficiently stabilized at the epigenetic level ( bending et al . , 2011 ; cohen et al . , 2011 ) . patients with t1d , have an increase in circulating il-17-producing cells ( honkanen et al . , 2010 ; 2011 ) , including foxp3 expressing th17 cells ( marwaha et al . , 2010 ) , monocytes that secrete th17 polarizing cytokines ( bradshaw et al . , 2009 ) , and islet - antigen specific th17 cells ( arif et al . , 2011 ) . there is also evidence that pancreatic lymph nodes from t1d patients have an increase in th17 cells ( ferraro et al . , 2011 ) and that islets from t1d patients , who died close to diagnosis , express il-17a , rorc , and il-22 ( arif et al . , 2011 ) . mechanistically il-17 enhances il-1 , ifn- , and tnf--induced apoptosis in human islets ( arif et al . , 2011 ) . we have also found that significantly elevated levels of cd8il-17 cells are detectable in the peripheral blood of a large subset of patients with t1d at disease onset ( marwaha et al . , 2010 ) . in the context of mounting correlative evidence that il-17-producing cells may be pathogenic in the early stages of t1d onset , clinical trials to test the effects of therapy with agents such as secukinumab or ustekinumab are warranted . the success of ustekinumab , a human il-12/23 monoclonal antibody , in patients with moderate to severe crohn s disease held promise for the targeting of the il-17 pathway to modulate this disease ( sandborn et al . , 2008 ) . however , the paradoxical exacerbation of crohn s disease in the clinical trial of a secukinumab , cast into doubt the pro - inflammatory role of th17 cells in the gut . whilst il-17 cell - producing cells are found in high numbers in inflamed mucosa in crohn s disease and ulcerative colitis patients , more recent data demonstrate that characterization on the basis of il-17 alone is insufficient to classify these cells as pathogenic . 2011 ) or co - express foxp3 ( ayyoub et al . , 2009 ; beriou et al . , 2009 ; miyara et al . , 2009 ; , 2011 ; ye et al . , 2011 ) , indicating the existence of multiple subsets of th17 cells with functional specialization ( figure 1 ) . the protective and pathogenic functions of th17 cells . depending on the local cytokine environment , different subsets of th17 cells arise and mediate distinct effector function . in the presence of il-23 , th17 cells seem to be pro - inflammatory and can either make ifn- themselves or work in concert with th1 cells to drive a positive feedback pathway of tissue damage such as that seen in psoriasis or ra . in crohn s disease , th17 cells can differentiate in the gut into protective or pathogenic th17 cells . in the presence of tgf- and il-21 , in retrospect , data from mouse models of colitis heeded a warning as to the protective role for th17 cells in crohn s disease . in the dextran sulfate sodium ( dss)-induced colitis model , administration of a neutralizing il-17a antibody ( ogawa et al . , 2004 ) , deletion of il-17a ( yang et al . , 2008b ) , or of il-22 ( zenewicz et al . , 2008 ) in contrast , il-17f - deficient ( yang et al . , 2008b ) and il-21-deficient mice ( fina et al . , 2008 ) these data suggest there are non - redundant roles of il-17a versus f , and that , at least in the gut , il-21 rather than il-17a or il-22 may be a primary th17-derived pathogenic cytokine . first , il-17a improves barrier function by strengthening tight junctions after inducing claudin and mucin expression ( kinugasa et al . , 2000 ; chen et al . , 2003 ) . second , il-22 improves barrier function by inducing epithelial cell proliferation ( brand et al . , 2006 ) and enhancing goblet cell restoration and mucus production ( sugimoto et al . , 2008 ) . also , a novel suppressive th17 subset dubbed regulatory th17 ( rth17 ) cells has recently been described . ( 2011 ) used a cd3-antibody strategy to induce mucosal tolerance , th17 cells were recruited to the gut but then re - programmed into suppressive , foxp3-negative , rth17 cells . the function of rth17 cells depends on il-10 , tgf- , and ctla-4 , and does not occur in ccr6-deficient mice where th17 are not recruited to the gut . the latter data indicate that the mucosal immunity micro - environment is critical for the development of rth17 cells . different flavors of th17 differentiation , ranging from highly pro - inflammatory to suppressive , result from different cytokine micro - environments in various diseases . th17 cells can no longer be identified solely on the production of il-17a since the combination of co - secreted cytokines is key to defining their effector function . moreover , il-17 is not only produced by th17 cells , and under certain conditions  t cells ( stark et al . , 2005 ) , cd8 t cells ( shin et al . , t follicular helper cells ( cua and tato , 2010 ) , lymphoid tissue induced ( lti ) cells ( cupedo et al . , 2009 ) , and nkt cells ( michel et al . we must therefore start to redefine the partial role that th17 cells play in il-17-guided immune response . an additional consideration is their potential for plasticity and co - secretion of cytokines that define other th cell lineages ( e.g. , ifn- ) , although this is more likely a transient rather than permanent change based on epigenetic analysis ( bending et al . , 2011 ; cohen et al . , 2011 ) . in summary , the notion that th17 cells are purely pro - inflammatory cells is mistaken , rather these cells mediate a diverse set of responses in infection , autoimmunity , and immunodeficiency . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
in 2005 a newly discovered t helper cell subset that secreted interleukin ( il)-17 became the center of attention in immunology . 
 initial studies painted th17 cells as the culprit for destruction in many different autoimmune and auto - inflammatory diseases . subsequently , 
 the discovery of patients with primary immunodeficiencies in the il-17 pathway taught us that th17 cells have a critical role in defense against certain fungal and bacterial infections . 
 moreover , the paradoxical exacerbation of crohn s disease in the clinical trials of a secukinumab ( ain457 ) , a fully human neutralizing antibody to il-17a , has cast into doubt a universal pro - inflammatory and harmful role for th17 cells . 
 evidence now suggests that depending on the environment th17 cells can alter their differentiation program , ultimately giving rise to either protective or pro - inflammatory cells . in this review 
 we will summarize the evidence from patients with immunodeficiencies , autoimmune , or auto - inflammatory diseases that teaches us how the pro - inflammatory versus protective function of th17 cells varies within the context of different human diseases .