in our rush to embrace th17 cells as the purveyors of tissue damage , we should not forget that cytokines produced by th1 cells and other cell types are critical in promoting various forms of inflammation . administration of ifn- , for example , worsened disease in patients with ms ( 13 ) . and blocking tumor necrosis factor ( tnf ) , which can be produced by various cell types , is a gold standard for treatment of diseases now thought to be driven largely by th17 cells , including ra , crohn 's disease , and various forms of psoriasis ( 1 ) . furthermore , type i ifns , which are therapeutic in ms ( 14 , 15 ) , are pathogenic in systemic lupus erythematosus ( 16 ) . it is worth noting that the role of il-17 in these major human diseases is much less well understood than tnf , ifn- , or type i ifns . ex vivo studies have also suggested that cytokines of the th1/th2 axis are critical determinants in mycobacterial diseases ranging from tuberculoid leprosy , which is primarily driven by il-12 and th1 cells , to lepromatous leprosy , which is mediated by th2 cells ( 17 ) . and although th17 is a welcome addition to our understanding of immune - mediated tissue damage , we still need the th1/th2 axis and other inflammatory mediators to explain many aspects of human autoimmune , allergic , and infectious diseases . in a recent issue of the jem , luger et al . ( 7 ) demonstrated that il-17 and il-23 , a cytokine that drives expansion of th17 cells , are important in the pathogenesis of eau , a model that reflects many aspects of both infectious and autoimmune uveitis in man . in that study , administration of antibodies against il-17 inhibited the development of eau after immunization with the retinal antigen intra - retinal binding protein ( irbp ) in complete freund 's adjuvant ( cfa ) , and also reversed established disease ( 7 ) . antibodies against il-23 also aborted the development of eau in this model , but only when given early in the disease ( fig . 1 a ) . blocking il-23 was no longer effective by day 7 , a time when t cells capable of inducing uveitis were already present . the authors thus concluded that il-23 is important for the priming of uveitis - inducing t cells , but not for their effector function . supporting a role for il-23 in eau induction , mice lacking the il-23 subunit p19 or p40 , which is also shared by il-12 , were protected against disease . mice lacking the il-12only subunit p35 , by contrast , were more susceptible to eau than were wild - type mice ( fig . 1 a ) . finally , transfer of in vitro  polarized , irbp - specific th17 cells into recipient mice triggered eau , even in the complete absence of ifn- ( fig . there was a significant reduction of eau in p19 and p40 knockout mice , with a significant increase in eau in p35 knockout mice compared with wild type . antibody blockade of il-17 reduced disease when given either during disease induction or after disease onset , whereas antibody blockade of il-23 reduced disease only when administered during disease induction . transfer of th1-polarized , irbp - specific cd4 t cells induced eau ( top ) . in this model , blocking il-17 had no effect on disease and blocking ifn- ameliorated disease . transfer of th17-polarized , irbp - specific cd4 t cells induces eau ( bottom ) , and , in this model , disease was equivalent when cells were transferred into ifn-deficient mice . irbp - pulsed mature dendritic cells were injected into mice , followed by pertussis toxin at day 2 . in this model , disease was decreased in ifn-deficient mice , despite an increased production of il-17 in the central nervous system as compared with wild - type mice . these findings in eau are similar to studies in eae , in which chronic disease is reduced in il-17 mice , although these mice still develop acute paralysis of their hind limbs ( 18 ) . adoptive transfer of myelin - reactive t cells from il-17 mice into wild - type mice also leads to much milder eae , as measured by incidence and severity of paralysis , compared with transfer of myelin - reactive t cells from wild - type mice ( 18 ) . other data from luger et al . , however , suggested that eau can also develop in the absence of th17 cells . transfer of a th1 clone specific for irbp , for example , caused severe disease in the absence of il-17 production ( fig . moreover , disease severity in response to immunization with irbp plus cfa was comparable in wild - type and il-17deficient mice ( 7 ) . it should be noted that many investigators equate the loss of il-17a in the il-17 mice ( 7 ) with a complete loss of th17 cells , but these cells also produce other cytokines , including il-17f , il-21 , and il-22 . although luger et al . conclude that the development of eau in il-17 mice required an ifn-producing effector t cell , they did not formally rule out a role for other th17 cytokines ( 7 ) . these results are difficult to interpret given other studies showing a protective role for ifn- in eau . neutralization of ifn- has been shown to exacerbate eau , just as it does eae ( 46 ) . furthermore , eau develops efficiently in mice depleted of ifn- , and , perplexingly , recombinant ifn- has been shown to protect against disease ( 19 , 20 ) . how , then , could an ifn-producing effector cell be important for the pathogenesis of eau , if recombinant ifn- is itself protective ? akin to the anomalies and paradoxes seen with th1 cells in eae , these results are probably telling us something highly important , although we do not yet have enough knowledge to explain it . but the data certainly conflict with the notion of il-17 as a master mediator of tissue damage , at least in eau . went on to induce eau by immunizing mice with irbp - pulsed dendritic cells , a model that is independent of cfa ( fig . the disease was characterized by an influx of t cells that produce large amounts of ifn- but little il-17 . and ifn-deficient mice immunized with irbp - pulsed dendritic cells were protected against disease despite the robust production of il-17 ( 7 ) . it is possible that the use of adjuvants in certain animal models of autoimmune disease , such as eae , eau , and collagen - induced arthritis , might skew the importance of il-17 . indeed , the presence of adjuvants that , like cfa , contain killed mycobacteria might provide a critical clue to explain the discrepancies between different models . in this issue , kroenke et al . show that adoptive transfer of either th1- or th17-polarized myelin - reactive t cells induces eae ( 8) . ascending paralysis ensued in both models , but the cellular infiltrate induced by th17 cells was rich in neutrophils , whereas macrophages predominated the th1-induced infiltrate  a pathological picture similar to ms , in which neutrophilic infiltration is rare . the pathology seen with il-17induced eae was reminiscent of that seen in acute disseminated encephalomyelitis , and other rare demyelinating conditions such as marburg 's disease , and also resembles certain aspects of neuromyelitis optica neuromyelitis optica is also similar to th17induced eae in that the pathology is most intense in the spinal cord and optic nerves . ( 9 ) showed that eae is most intense in the brain when th17/th1 ratios are high , whereas inflammation is focused on the spinal cord when th17/th1 ratios are more widely varied . the overall picture that emerges suggests that eae has a variety of histological and anatomical manifestations depending on the cytokines produced by the disease - inducing t cells ( 8 , 9 ) . thus , one can not conclude at all that eae is driven by th17 cells . the data from kroenke et al . ( 21 ) indicated that even th2 cells can induce eae in rag - deficient mice . in that study , such pathology replete with eosinophils , typical of allergic disorders , would be worthy of the original term for eae ,  experimental allergic encephalomyelitis .  other cytokines like osteopontin drive the production of ifn- ( 22 , 23 ) , and osteopontin has also recently been shown to drive the production of il-17 ( 24 ) . osteopontin is critical in triggering relapses of eae and is elevated in the plasma of patients suffering ms relapses ( 25 ) . is it thus possible that osteopontin is the main driver of tissue damage and ms relapses , and not ifn- or il-17 ? it can hardly be concluded at this point that th17 is the sole driver of tissue damage in ms or eae . another issue that must be considered is that il-17 would not have evolved if it only did harm . the protective side of il-17 was demonstrated in a recent study of mycobacteria tuberculosis infection , in which il-17 was required to recruit protective ifn-producing cd4 t cells into the lung ( 26 ) . in an asthma model , neutralization of il-17 increased eosinophilic infiltration during the effector phase of disease , and administration of recombinant il-17 diminished airway hyperreactivity and reduced the numbers of eosinophils and lymphocytes in bronchial lavage ( 27 ) . in this model of asthma , il-17 thus appears to be a negative regulator of established disease ( 27 ) . how can we continue to call the th17 pathway the critical mediator of immune - mediated tissue damage with such counter examples from autoimmunity , infectious disease , and allergic disease ? the ultimate significance of the th17 pathway in human disease remains unclear , and we are only now clarifying the details of the th17 pathway in humans . the first analyses of the th17 pathway came from studies of experimental diseases in mice , and the first studies on the th17 in man revealed significant differences . as natalie angier wrote in her elegant book the canon ,  whether sizing up new acquaintances or seizing on novel ideas , we remain forever at the mercy of our first impressions  ( 28 ) . in immunology ( at least these days ) , our first impressions often come from mice . again to quote angier , we should analyze the source of our misconceptions , and then we  have a chance of amending , remodeling , or blowtorching them as needed , and replacing them with a closer approximation of science 's approximate truths  ( 28 ) . the parallels between mouse and man first diverged in defining a role for transforming growth factor ( tgf)- in the differentiation of th17 cells . in mice , il-6 and tgf- two initial human studies , however , showed that il-6 and il-1 ( produced by monocytes or conventional dendritic cells ) , but not tgf- , were critical for the priming of th17 responses ( 29 , 30 ) . in one of those studies , tgf- suppressed il-17 production ( 29 ) . more recent data , however , revealed that tgf- , il-1b and il-6 , il-21 , or il-23 ( in serum - free conditions ) could induce il-17 production from naive human cd4 t cells from umbilical cord blood ( 31 ) . induced il-17 expression , but this suppression was relieved in the presence of inflammatory cytokines . another study showed that tgf- was essential , along with il-23 , il-1 , and il-6 for th17 differentiation ( 32 ) . yet another showed that tgf- enhanced il-17 in peripheral t cells ( 33 ) . at this point it appears that il-1 and il-6 drive il-17a production from central memory cd4 t cells , whereas tgf- and a constellation of other inflammatory cytokines promote the differentiation of naive cd4 t cells into th17 cells ( 34 ) . local induction of tgf- in mouse brain , for example , leads to induction of eae ( 36 ) , and its pharmacologic suppression reverses paralytic disease ( 37 ) . tgf- signaling in the brain leads to increased production of il-6 , which then enhances inflammation ( 37 ) . tgf- is elevated in chronic ms lesions , in which there is also intense production of il-17 from astrocytes and oligodendroglia ( 38 ) . thus , tgf- might promote il-17 production during the chronic active phase of ms ( 9 , 38 ) . studies in humans have also revealed the existence of t cell clones in the intestines of patients with inflammatory bowel disease that produce both il-17 and ifn- , and are thus designated th1/th17 cells . these dual producers can also be found in eae lesions in mice ( 39 ) and express both the th17-inducing transcription factor ror-t and the th1-inducing transcription factor t - bet . immunologists ought to be restrained in attributing too much to the th17 pathway at this stage . the plentiful exceptions outlined in this commentary suggest that its signature function as the mediator of organ - specific tissue damage in autoimmunity and other forms of pathology should be refined . exceptions always teach us something important , as we have learned from our evolving understanding of the th1/th2 paradigm ( 1 ) . the th17 pathway has many divergent roles in models of autoimmune , infectious , and allergic disease . indeed , il-17 is not even a purely th17 cytokine because it is also made by macrophages ( 40 ) , astrocytes ( 41 ) , oligodendroglia ( 41 ) , uterine fibroids ( 42 ) , and corneal epithelial cells on the surface of the eye ( 43 ) . emerging data indicate that molecules such as osteopontin drive both th1- and th17-mediated tissue damage ( 2225 ) . we might thus be heading toward the conclusion that no single molecule or th pathway dominates and that there is no hierarchical scheme at all . it is difficult to understand how so many immunologists developed such exuberant enthusiasm for th17 in the first place , placing it in a starring and paramount role for all immune - mediated tissue damage . one of the groups who was instrumental in the discovery and elucidation of this pathway recently reviewed the subject with a balanced perspective ( 2 ) . they enumerated the multiplicity of  inconvenient truths  that befuddled this role for th17 when they asked ,  but are th17 cells the only effector cells capable of inducing organ - specific autoimmunity ? mice deficient in t - bet and stat-4 , and thus lacking th1 cells ( 45 , 46 ) , have overwhelmingly large numbers of th17 cells ( 47 , 48 ) and yet are resistant to eae ( 4749 ) . do those data suggest that th1 cells are pathogenic and th17 cells are not ? the truth is probably somewhere in the middle . for many reasons , we support the idea that both th1 and th17 cells are capable of inducing autoimmunity  ( 2 ) . an emerging conclusion is that tissue damage and protection are nuanced and are governed by multiple / redundant molecular interactions that involve many cytokines , including the type i ifns , and other molecular cascades including , for example , the coagulation pathway ( 50 ) . thus , we should reserve our judgment about th17 and not jump to conclusions as we did with the th1/th2 paradigm ( 1 ) .
some immunologists have characterized t helper ( th)17 t cells as the master mediators of tissue damage in a variety of pathological conditions . 
 new data now demonstrate that th1 and th17 t cells are independently capable of inducing disease in two established models of autoimmunity . 
 thus , the role of th17 cytokines as the central mediators of pathological tissue damage seems to require clarification .