the th1/th2 cell dichotomy and the essential role of the cytokine environment in driving their differentiation are well accepted .
interleukin ( il)-12 , acting via the transcription factors stat4 and t - bet , drives the differentiation of naive cd4 t cells into interferon ( ifn)- producing th1 cells , whereas il-4 , acting via stat6 and gata3 , drives the differentiation of il-4producing th2 cells .
th1 cells are responsible for the cell - mediated elimination of intracellular pathogens , whereas eradication of helminthic infestations is dependent on adequate th2 responses .
however , the immunopathogenesis of autoimmune disease does not fit quite so neatly into this dichotomy .
cd4 t cells can also differentiate into cells that produce the immunosuppressive cytokines il-10 and tgf , so - called th3 cells , and can become  adaptive  regulatory t cells .
studies of experimental autoimmune encephalophalomyelitis and adjuvant - induced arthritis have pointed to the importance of yet another th cell subset , which produces il-17 and is now termed th17 cells .
although this population of t cells has been implicated in the exacerbation of autoimmune pathology ( 13 ) , the role of th17 cells in host defense remains to be elucidated .
the subject of two papers in the issue ( owyang et al . , p. 843   and
fallon et al . , p. 1105 ) is the th2-like cytokine , il-25 , which as a member of the il-17 family is also known as il-17e .
structurally , this family of six cytokines ( il-17a - f ) is thought to form cystine knots and in this respect is related to other better known cytokines such as tgf and platelet - derived growth factor .
il-17 ( il-17a ) was originally reported to be produced mainly by effector and memory cd4 t cell subsets , but has more recently been suggested to be more widely expressed ( 6 , 7 ) .
il-17f is located adjacent to il-17 on mouse chromosome 1 ( human chromosome 6 ) , and although it seems to be regulated in a similar manner , it may be more widely expressed than il-17 . less well studied are il-17b , il-17c , and il-17d , which are thought to be expressed in a variety of nonhematopoeitic tissues , although il-17d is reported to be produced by cd4 t cells ( 8) .
five il-17 receptors have been identified , but only the receptors for il-17/il-17f and il-25 have been characterized .
the il-17 receptor is structurally distinct from other cytokine receptors , and engagement of the receptor activates map kinases and nf-b . signaling via il-25 is reported to be dependent on the adaptor molecule traf6 ( 9 ) . with respect to their biological actions , il-17 and il-17f are most intensively studied .
these cytokines evoke inflammation largely by inducing the production of chemokines , as well as granulocyte colony - stimulating factor and granulocyte macrophage colony - stimulating factor , with the subsequent recruitment of polymorphonuclear leukocytes . in some settings , however , il-17 or il-17f  induced inflammation is dominated by macrophages ( 10 ) .
the induction of matrix metalloproteinase production by epithelial cells may be another important proinflammatory function of il-17 ( 11 ) .
abundant data point to pathogenic roles of il-17 in models of immune - mediated disease and in human autoimmune disorders .
less well defined are the beneficial roles of il-17 family cytokines in host defense , although recent data indicate il-17 is important for resistance against klebsiella pneumoniae and mycobacterium tuberculosis ( 1214 ) . unlike il-17 and il-17f , il-25 is produced by th2 cells and mast cells ( 15 ) .
administration of recombinant il-25 ( ril-25 ) to mice has been shown to evoke an inflammatory response characterized by the overproduction of th2 cytokines , hyperproduction of immunoglobulins iga and ige , overproduction of mucus , epithelial cell hyperplasia , and eosinophilia .
furthermore , the observed pathology was dependent on the classical th2 cytokines il-4 and il-13 , as shown by the lack of effect of administering ril-25 to mice that lack these cytokines or their cognate receptor .
th17 cells are now thought to be a separate lineage of effector th cells , but the optimal recipe to differentiate th17 cells in vitro remains somewhat unclear ( 10 , 1618 ) , and the in vivo requirements for their differentiation have yet to be firmly established .
several groups have pointed to the importance of il-23 as a critical ingredient for the generation and/or maintenance of this lineage ( 10 , 13 , 1720 ) .
it should be kept in mind that because of its structural similarity to il-12 ( p35/p40 ) ( 2124 ) il-23 ( p19/p40 ) also has the potential to induce a th1-like response .
recently , another group has come up with a different recipe to make th17 cells that involves a milieu of cytokines produced by lipopolysaccharide - activated dendritic cells ( namely il-1 , il-6 , and tnf- ) and the presence of tgf ( 25 ) .
these findings not only illustrate that there is overlap in the groups of cytokines that induce different populations of cd4 t cells , but also emphasize that a particular cytokine , in this case tgf , may have both proinflammatory ( th17-inducing ) and antiinflammatory ( th3-inducing ) roles , depending on the circumstances .
in this issue , two new studies by owyang et al . ( 4 ) and fallon et al . ( 5 ) show that il-25 mice have increased susceptibility to the parasitic helminthes , trichuris muris , and nippostrongylus brasiliensis .
both groups found that the antihelminth activity of il-25 depends on its ability to induce the th2-associated cytokines il-4 , il-5 , and il-13 . in the case of t. muris infection ,
the susceptibility of il-25 mice was associated with impaired il-4 and il-13 production and reduced trichuris - specific igg1 and total ige . in addition , chronically infected il-25 mice had exacerbated pathology , which was characterized by severe inflammation and disruption of intestinal epithelial structure , and was associated with increased production of ifn- , il-17 , and total igg2a .
thus , in addition to an essential role in driving antihelminth th2 responses , this study implies an antiinflammatory role for il-25 in suppressing th1 and th17 responses .
in contrast , fallon et al . ( 5 ) found that il-25 was not absolutely required for the generation of th2 responses in n. brasiliensis infection , but that il-25 was important for the timely resolution of the infection . when il-25 mice were challenged with n. brasiliensis , the polarization of the th2 response , manifested as enhanced il-4 , il-5 , and il-13 production , was delayed .
ifn- antibodies reduced the worm burden and enhanced th2 responses in trichuris - infected il-25 mice , as well as in the naturally susceptible akr mouse strain .
thus , il-25 does not appear to be absolutely essential for th2 responses to some helminthes , and may promote host defense by inhibiting expression of type 1 cytokines . which cell types produce il-25 and which cell types respond to it ? using mice that have the reporter lacz knocked into the il-25 locus , owyang et al .
it was constitutively expressed by cd4 and cd8 t cells in the gut but was not expressed in a variety of innate immune cells .
these data hint at the possible existence of effector t cells that selectively produce il-25 ( a putative th25 lineage ) , which may play a specific role in mucosal immunity . in their study , fallon et al .
( 5 ) report that the target of il-25 is a nonlymphoid c - kit cell present in the draining lymph node .
the finding that the il-25mediated expulsion of n. brasiliensis was t and b cell independent emphasizes the importance of this nonlymphoid population .
using mice in which the reporter egfp was knocked into the il-4 locus , fallon et al .
( 5 ) show that nonlymphoid c - kit cells are major producers of il-4 during infection and their appearance in the draining lymph node precedes the expansion of il-4producing cd4 cells .
these findings are consistent with previous work using ril-25 , which indicated that this cytokine does not have direct effects on differentiating t cells , but rather that its action requires nonlymphoid cells .
as all good studies should , these two papers raise more questions than they answer ( 4 , 5 ) . together
the findings are of considerable interest because , compared to the seemingly clear cut mechanisms involved in th1 cell differentiation , the factors that drive th2 cell differentiation have been more difficult to understand . both groups convincingly show that il-25 is an important regulator of th2 responses and host defense . whether il-25 is produced by t cells for t cells or by apcs for nonlymphoid effector populations it indisputably serves to enhance il-4 production resulting in amplification of th2-mediated immunity .
these reports also indicate that il-25 controls inflammation during helminth infection and dampens counterproductive th1 responses , independent of il-25 's effects on th2 cell differentiation .
the duality of il-25 activity mirrors that of the well - known immunosuppressive cytokine tgf , which , as mentioned , induces the polarization of proinflammatory th17 cells ( 25 ) .
the paradigm of th1 and th2 responses is firmly supported by an immense amount of in vitro data but , more importantly , is substantiated in many infectious disease models and some autoimmune disease models . as the papers in this issue exemplify ( 4 , 5 ) , the generation of other t cell subsets in models of host defense is less clear cut ( fig .
ifn- promotes th1 cell differentiation by inducing t - bet , but inhibits both th17 cell and th2 cell differentiation ( 26 , 27 ) .
similarly , il-4 , by inducing gata-3 , inhibits th17 cell and th1 cell differentiation .
thus , it would appear that the generation of th1 , th2 , and th17 cells is carefully balanced .
in contrast to the well - described positive effects of ifn- and il-4 on their respective lineages , no data have been provided indicating that il-17 directly regulates th cell differentiation , either positively or negatively ( 27 , 28 ) .
furthermore , will we find that like th1 and th17 cells , il-25secreting cells are really a distinct lineage from th2 cells and subject to different modes of regulation ? to this end , the question of whether the putative th25 cell population expresses lineage - specific transcription factors that determine its cytokine production profile will likely be a focus of future studies .
further studies are also needed to understand and define the functional role of th17 and th25 cells as either primary effectors similar to th1 and th2 cells , or sentinel populations that promote or enhance more specific cell - mediated immunity in mucosal tissues .
one might envision a scenario in which pleiotropic cytokines such as il-17 , tgf , and il-25 not only potentiate early th responses and recruitment of cells to lymph nodes and tissues , but also regulate aberrant inflammatory responses during the resolution of infection . the ability of il-25 to limit th1-induced inflammation might be an example of the latter .
how all of this relates to human health and disease is less clear , and with future studies refined concepts of t cell differentiation will come to bear .
on pathogen challenge , cd4 t cells will differentiate into either ifn-producing th1 cells or il-4producing th2 effector cells , which directly cross - regulate each other .
two new reports now suggest that the il-17 family member il-25possibly produced by a population of t cells in the gut mucosa 
the target of il-25 may be a nonlymphoid c - kit population , which produces il-4 and in turn enhances th2 cell differentiation by cd4 t cells .
in addition , il-25 may have a direct role in inhibiting both th1- and th17-producing cells during helminth infection in order to limit the inflammatory response .
the extent to which il-25producing t cells are a distinct th lineage ( th25 ) or if il-25 production is a feature of many th2 cells will need further investigation . in conclusion , this is a very exciting time for t cell biologists . in the age of monarchies , the expression 
le roi est mort ; vive le roi  marked the passing of eras , ushering out one regime while introducing another .
the simple notion of a dualistic view of th1/th2 cell differentiation is moribund , but the era of new complexities of immunoregulation promises to provide better understanding of mechanisms of host defense and immune - mediated disease .
 in the dark ages of t cell biology , we considered two fates for differentiated cd4 + t cells : t helper ( th)1 and th2 cells . 
 now we know that the reality is much more complex and interesting . 
 the newest th cell subset produces the cytokine il-17 . 
 new evidence shows that the il-17related cytokine il-25 is essential for th2 responses in two infectious disease models . 
Cytokines driving Th cell differentiation
The IL-17 family
The Th17 lineage
Roles for IL-25 in host defense and controlling inflammation
New findings, new questions