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(Journal of Leukocyte Biology. 2003;73:49-56.)
© 2003 by Society for Leukocyte Biology

A unique role for IL-23 in promoting cellular immunity

Carla S. R. Lankford and David M. Frucht

Laboratory of Cell Biology, Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland

Correspondence: David M. Frucht, Building 29B, Room 3NN22, DMA/CBER/FDA, Bethesda, MD 20892. E-mail: frucht{at}cber.fda.gov


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ABSTRACT
 
Recent discoveries of interleukin (IL)-23, its receptor, and its signal-transduction pathway add to our understanding of cellular immunity. IL-23 is a heterodimer, comprising IL-12 p40 and the recently cloned IL-23-specific p19 subunit. IL-23 uses many of the same signal-transduction components as IL-12, including IL-12Rß1, Janus kinase 2, Tyk2, signal transducer and activator of transcription (Stat)1, Stat3, Stat4, and Stat5. This may explain the similar actions of IL-12 and IL-23 in promoting cellular immunity by inducing interferon-{gamma} production and proliferative responses in target cells. Additionally, both cytokines promote the T helper cell type 1 costimulatory function of antigen-presenting cells. IL-23 does differ from IL-12 in the T cell subsets that it targets. Whereas IL-12 acts on naïve CD4+ T cells, IL-23 preferentially acts on memory CD4+ T cells. This review summarizes recent advances regarding IL-23, providing a functional and mechanistic basis for the unique niche that IL-23 occupies in cellular immunity.

Key Words: IL-23R • IL-12 • IL-12R • Stat4


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INTRODUCTION
 
The differentiation of naïve CD4 T helper (TH) cells into effector cells is a defining process during immune responses [1 , 2 ]. TH1 effector cells produce interferon-{gamma} (IFN-{gamma}) and promote cellular immunity and protection against intracellular pathogens, whereas TH2 effector cells produce interleukin (IL)-4 and promote humoral immunity and protection against extracellular pathogens including helminths [1 , 2 ]. The expression of several key transcription factors is thought to be pivotal in TH differentiation. One of these transcription factors, the T-box transcription factor, T-bet, promotes TH1 differentiation and down-regulates TH2 responses [3 ]. In contrast, Gata binding protein 3 [4 ] and v-maf musculoaponeurotic fibrosarcoma oncogene homolog [5 ] promote TH2 differentiation and inhibit TH1 responses. Cytokine signaling is the other major regulator of TH differentiation. The cytokines IL-12 and IL-4 induce polarized TH differentiation, supporting TH1 and TH2 responses, respectively, and have been used classically for in vitro TH differentiation [1 , 2 ].

In addition to the classical promoters of TH differentiation, other cytokines play important roles in promoting cellular immune responses. For example, IFN-{gamma} directly induces T-bet expression, providing positive feedback during TH1 differentiation [6 ]. Furthermore, IL-12 and IFN-{alpha} use the signal-transduction molecule, signal transducer and activator of transcription (Stat)4, providing a mechanistic basis for their joint action in promoting TH1 differentiation [7 ]. We also now know that in addition to its p40 subunit, IL-12 shares most of its signal-transduction components [IL-12 receptor (R)ß1 subunit, Tyk2, Janus kinase (Jak)2, along with Stats1, -3, -4, and -5] with a newly described cytokine, now termed IL-23 [8 , 9 ]. These shared features likely explain the overlapping functions of IL-12 and IL-23 and introduce a unique role for IL-23 in promoting cellular immune responses in circumstances where IL-12 or its receptor is not present.


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IL-12 SHARES FUNCTIONS AND SIGNAL-TRANSDUCTION COMPONENTS WITH OTHER CYTOKINES
 
IL-12 is an important costimulatory cytokine, produced chiefly by antigen-presenting cells (APC) during cellular immune responses, that promotes the polarization of naïve T cells into TH1 cells [1 , 2 , 10 ]. Its importance in cellular immune responses is highlighted in humans and mice with genetic deficiencies in IL-12 or IL-12R components. Gene-targeted mice and humans with inactivating mutations in these genes have profound defects in cellular immunity and increased susceptibility to intracellular infections [11 12 13 14 15 ].

IL-12 plays an important role in promoting cellular immune responses; however, it is not absolutely required for TH1 polarization. IL-12 p35-/- [16 ], IL12-p40-/- [11 ], IL-12Rß1-/- [12 ], and IL-12Rß2-/- [13 ] mice show residual TH1 polarization following antigen stimulation. It is well known that other cytokines, including type I IFNs, are capable of promoting TH1 polarization [17 ]. It has been speculated that part of this overlap in function could be a result of shared use of cytokine receptor signal-transduction pathways; type I IFNs and IL-12 activate the signal-transduction molecule, Stat4 [7 ]. The use of Stat4 as a common signal-transduction component could explain similarities in the effects of type I IFNs and IL-12. Whether IL-12 or its receptor shares other components of the cytokine/receptor/signal-transduction network was, until recently, unknown, although this was consistent with the data generated from mice with targeted deletions of the subunits of the IL-12 heterodimer (Table 1 ).


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  		Table 1. Comparison of IL-12 p35-/- and p40-/- Mice in Selected Studies


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PHENOTYPES OF IL-12 p35-/- AND p40-/- MICE EXPOSED PUZZLING DIFFERENCES
 
As IL-12 comprises the p35 and p40 subunits, if both subunits were used exclusively by IL-12, one would expect that mice deficient in either of these subunits would have similar phenotypes. Indeed, in the first study directly comparing p35-/- and p40-/- mice, the two strains had very similar outcomes in a L. major infection model. Both had progressive lesions, and the lesions of wild-type mice resolved spontaneously. Although p35-/- mice had a lower parasite load than p40-/- mice in this study, the difference was reported not to be statistically significant [16 ].

Subsequent studies revealed clear distinctions between p35-/- and p40-/- mice (Table 1) . For example, p40-/- mice had much decreased TH1 immune responses (e.g., IFN-{gamma} production) in a cardiac allograft model compared with wild-type and p35-/- mice [18 ]. Moreover, p40-/- mice had increased susceptibility to C. neoformans compared with p35-/- mice, marked by increased mortality and organism burden [19 ]. Taken together, these findings indicated that p40 deficiency results in a more severe immunodeficiency phenotype than p35 deficiency, suggesting that p40 has a function outside of its role as a component of IL-12. Even at the time of these studies, the authors speculated that this immune-enhancing activity might be a result of an undiscovered partner of IL-12 p40 [18 ]. We now know that IL-12 shares its p40 component with a newly discovered cytokine, IL-23 [8 ]. Moreover, studies reported subsequent to the discovery of IL-23 demonstrate increased susceptibility of p40-/- mice to S. enteritidis [20 ], F. tularensis [23 ], and mycobacterial infections [21 , 22 ] compared with p35-/- mice. Taken together, these studies establish a unique role for the IL-12 p40 subunit, and likely for IL-23, in promoting cellular immunity.


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IL-23: A MEMBER OF THE IL-6 CYTOKINE FAMILY
 
The IL-23 p19 component was first identified and characterized during sequence database searches for members of the IL-6 cytokine family [8 ]. At the sequence level, IL-23 p19 is most closely related to the IL-12 p35 subunit [8 ]. This similarity extends to functional characteristics as well, as p19 forms a disulfide-linked heterodimer with the IL-12 p40 subunit to form IL-23 [8 ]. In this manner, the p40 subunit is shared between IL-12 and IL-23, a characteristic more consistent with cytokine receptor subunits than cytokines [25 , 26 ]. It is interesting that p40 shares sequence homology not with cytokines but with their receptors (e.g., IL-6R, ciliary neurotrophic factor receptor), a finding that could explain the origin of its use as a common subunit [25 , 26 ].


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IL-23R COMPLEX COMPRISES IL-12Rß1 AND A NOVEL IL-12Rß2-LIKE CHAIN
 
At the time of the original cloning of IL-23, it was demonstrated that IL-23 binds to cells expressing IL-12Rß1 but not to those expressing IL-12Rß2 [8 ]. As the IL-12Rß2 chain is critical for signal transduction, the presence of another IL-23R complex component in addition to IL-12Rß1 was predicted. The unique IL-23R complex component gene was isolated from a retroviral cDNA library generated from the Kit225 cell line, a cell line that proliferates in response to IL-23. Ba/F3 cells expressing IL-12Rß1 were transduced and screened for clones that proliferated in the presence of IL-23. In this manner, the cDNA corresponding to the IL-23R complex-specific subunit (now termed IL-23) was identified. Furthermore, it was demonstrated that human (h)IL-23R is a 629 amino acid type I transmembrane protein, with sequence homology with IL-12Rß2 and gp130. Remarkably, the gene for hIL-23R is located on chromosome 1p31.2–32.1, very close to IL-12Rß2, suggesting that a gene duplication occurred sometime during evolution. A functional murine (m)IL-23R has also been discovered, based on its homology with the human IL-23R gene sequence. The murine counterpart of hIL-23R is 644 amino acids in length and has 84% sequence homology with the protein-coding regions of the hIL-23R gene [9 ].

Structurally, hIL-23R shares many features with hIL-12Rß2, including a signal sequence, an immunoglobulin-like domain, and two cytokine receptor domains. hIL-12Rß2, however, is considerably longer, having three extracellular, membrane-proximal fibronectin type III domains that are not present in IL-23R. The sequence motif, WQPWS, is present in the membrane-transmembrane proximal cytokine receptor domain, likely corresponding to the WSXWS signature motif characteristic of cytokine receptors. The cytoplasmic portion of hIL-23R comprises 252 amino acids, including seven tyrosine residues. Protein sequence analysis of this cytoplasmic portion reveals three potential Src homology 2 domain-binding sites and two potential Stat-binding sites. The importance of these sites is highlighted by the 100% amino acid identity in the mouse and hIL-23R proteins within these motifs [9 ]. Nevertheless, future studies will be required to determine whether in fact these potential sites are necessary for IL-23R signal transduction.


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IL-23R SIGNAL TRANSDUCTION: PRELIMINARY STUDIES REVEAL SIMILARITIES WITH IL-12R
 
IL-23 binds the IL-23R complex, composed of IL-23R and IL-12Rß1 [9 ]. Upon engaging IL-23, IL-12Rß1 and IL-23R associate, marking the beginning of the IL-23 signal-transduction cascade, many of whose components are now known (Fig. 1 ) [9 ]. Assuming that the IL-23 signal-transduction cascade parallels those of other cytokines [27 , 28 ], ligand binding leads to activation of Jaks. The Jaks then phosphorylate the IL-23R at key sites, forming docking sites for the Stats. Subsequently, the Jaks phosphorylate the Stats, which dimerize and translocate to the nucleus where they activate target genes.



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  		Figure 1. Stat4 activation is a common feature of IL-23, IL-12, and IFN-{alpha} signal-transduction pathways. IL-23 signal transduction is very similar to that of IL-12; they both use IL-12Rß1, Jak2, Tyk2, Stat1, Stat3, Stat4, and Stat5. The signal-transduction apparatus of IFN-{alpha} is markedly different than IL-23, using an entirely different receptor complex. Nevertheless, stimulation with IFN-{alpha} results in Stat4 activation as well. This common feature may explain similarities in TH1 function among IL-12, IL-23, and IFN-{alpha}.

Even before the cloning of the IL-23R, it was known that IL-23 stimulation leads to phosphorylation and activation of Stat4, joining the very short list of cytokines (e.g., IL-12 and IFN-{alpha}) [7 , 29 ], which use this transcription factor [8 ]. This finding is consistent with analysis of the IL-23R sequence, which reveals close sequence similarity between the region surrounding Y484 and the motifs in IL-12Rß2 demonstrated in prior studies to bind Stat4 [30 , 31 ]. The similarity between IL-23R and IL-12Rß2 is further highlighted by shared use of Jak2, Tyk2, and the overall pattern of Stat activation (Stat1, Stat3, Stat4, Stat5). The major difference between the signal-transduction cascades of the two cytokines appears to be in the level of Stat4 phosphorylation; IL-23 induces much less phosphorylation of Stat4 than does IL-12. Additionally, there is preliminary evidence that the majority of activated Stat4 may heterodimerize with Stat3 following IL-23 stimulation (Fig. 1) . This contrasts signal transduction following IL-12 stimulation, which is characterized by a predominance of Stat4 homodimers, perhaps indicating that IL-12 and IL-23 may act on different target genes [9 ]. However, the significance of these differences in Stat4 interactions following activation by IL-12 or IL-23 is unknown.


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THE EXPRESSION PATTERN OF IL-23 AND ITS RECEPTOR IDENTIFIES POTENTIAL SITES OF ACTION
 
As there appears to be much similarity in the signal-transduction pathways between IL-23 and IL-12, it may be the case that unique functions of these cytokines are determined at a different level of regulation. For example, differences in expression patterns between the cytokines or their receptors could provide a mechanistic basis for the functional niches that these cytokines occupy.

Experiments reported in one study describing transgenic mice overexpressing IL-23 p19 reveal that regulation of its production in hematopoietic cells is critical. Mice that express this gene ubiquitously under control of the ß-actin promoter have defects in growth and fertility and have multi-organ inflammation characterized by lymphocyte and macrophage infiltration. Adoptive transfer experiments of transgenic bone marrow cells into normal host transfer the disease phenotype, demonstrating that this inflammatory phenotype results from overexpression in hematopoietic cells. In contrast, mice that overexpress IL-23 p19 under a liver-specific promoter do not display this phenotype, indicating that its biological activity requires cell-specific expression [32 ].

Similar to IL-12 p35, IL-23 p19 is poorly secreted when expressed alone and requires IL-12 p40 for optimal expression. Although p19 is produced by macrophages, dendritic cells (DC), T cells, and endothelial cells, the data available thus far indicate that only APC concomitantly express p40 and are presumably capable of producing functional IL-23 [8 ]. Whether IL-23 is expressed by other cell types following stimulation is unknown but is an area of active investigation. It would be predicted to be expressed during infections, as IL-23 p19 action has been shown indirectly to be important in controlling infections in experiments with IL-12 p40-/- and p35-/- mice. This has been confirmed in recent studies showing that IL-23 p19 is induced by bacterial products that signal through Toll-like receptor-2 [33 ] and that IL-23 p19 and IL-12 p40 are concomitantly expressed in tissues from mice infected with mycobacteria in vivo [21 , 22 ]. However, it has not yet been determined whether infection-induced IL-23 production is confined to APC or whether IL-23 can be generated from different cells types, each secreting one of the IL-23 subunit molecules.

Interpretation of the expression pattern of the IL-23R complex is more straightforward, as IL-23-dependent signaling would predictably require the simultaneous presence of both receptor subunits. Both components of the IL-23R complex are expressed in CD4+CD45RBlo memory cells but not in naïve CD4+CD45RBhigh cells. This contrasts with IL-12Rß2 expression, which is much higher in the CD4+CD45RBhigh population. Additionally, both components are similarly expressed in natural killer cells, where the function of IL-23 is yet to be established. Furthermore, the unique IL-23R component is expressed in murine bone marrow macrophages and DC, although this is accompanied by very little IL-12Rß1 expression. However, IL-12Rß1 and the IL-23R unique component are expressed simultaneously in cells stimulated by IFN-{gamma} in the presence of blocking anti-IL-10R antibody in vitro, demonstrating that an intact IL-23R complex is expressed by murine macrophages under certain conditions. Thus far, the IL-23R complex has not been detected in human APC in conditions that parallel those in which it is induced in murine cells, but the possibility of its expression cannot be excluded based on the data available presently [9 ]. Most importantly, critical data regarding the expression profile of the IL-23R complex components in vivo are still lacking.


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IL-23 ACTS ON MEMORY T CELLS
 
Differences in expression between the IL-23 and IL-12R complexes provide a basis for their differing actions on naïve and T cell receptor-activated T cells. Naïve murine T cells, which express IL-12Rß2 and not IL-23R, proliferate and produce IFN-{gamma} in response to IL-12 stimulation but not in response to IL-23 stimulation [8 ]. Murine memory CD4+ cells, in contrast, express IL-23R and relatively low levels of IL-12Rß2 [9 ]. This may explain why memory CD4+ T cells in the mouse proliferate in response to IL-23 and not in response to IL-12 [8 ]. The actions of IL-12 and IL-23 are similar in humans, with the exception that IL-12 and IL-23 can act on memory CD4+ T cells to increase proliferation and IFN-{gamma} production [8 ]. Taken together, these data suggest that one of the actions of IL-23 is to sustain cellular immunity by promoting the survival and effector cytokine production of TH1 memory cells. This may explain why mice lacking the p40 subunit of IL-12/23 are unable to clear intracellular infections such as those caused by Francisella [23 ].


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IL-23 MODULATES DC COSTIMULATORY FUNCTION
 
The cell targets of IL-12 and IL-23 are not restricted to lymphoid cells; both cytokines act on myeloid APC as well. For example, IL-12 acts on murine macrophages and DC to induce production of IFN-{gamma} in a Stat4-dependent manner, enhancing their costimulatory function [34 , 35 ]. Mixed lymphocyte reactions involving IFN-{gamma}-/- DC and wild-type CD4+ T cells result in a significantly reduced IFN-{gamma} production compared with those involving wild-type DC and CD4+ T cells, demonstrating a role for IFN-{gamma} production by APC [34 ]. The importance of IFN-{gamma} production by APC in vivo is confirmed by the profound defect of peptide-loaded IFN-{gamma}-/- DC in promoting TH1 differentiation when adoptively transferred into recipient wild-type mice [36 ].

Similarly, IL-23 binds to mDC and acts to increase IFN-{gamma} production in a dose-dependent manner, albeit to a lesser extent than IL-12. Moreover, IL-12 and IL-23 up-regulate IL-12 production in DC to equivalent levels. The importance of IL-23 in costimulation is highlighted by experiments demonstrating that IL-23 primes DC for promoting DTH responses to synthetic peptides in vivo. IL-23 binds to CD8- and CD8+ DC equally, inducing equivalent amounts of IL-12 in each subset. This is consistent with the finding that IL-23 exerts similar adjuvant effects on each of these DC subsets when they are primed to present a synthetic peptide in vivo. In this respect, IL-23 differs from IL-12, as IL-12 provides adjuvant effect in priming experiments involving peptide-loaded CD8- DC and not those involving CD8+ cells [37 ]. The basis for the differing actions of IL-12 on the DC subsets is unclear. As both DC subsets are capable of responding to IL-12 by increasing IFN-{gamma} production, one would predict that there exist differences between the two DC subsets in the signal-transduction pathways downstream of the IL-12R complex. Presumably, these differences do not exist in the IL-23 signal-transduction cascade in CD8- and CD8+ DC.


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IL-23 ENHANCES PROTECTION AGAINST INTRACELLULAR PATHOGENS
 
A comparison of data from p35-/- mice (IL-12-deficient) with p40-/- mice (IL-12- and IL-23-deficient) provides indirect evidence that IL-23 has an important function in the control of certain intracellular infections, including those caused by Cryptococcus [19 ], Salmonella [20 ], Francisella [23 ], and mycobacteria [21 , 22 ] (Table 1) . Additionally, these studies indicate a role for IL-23 in the alloreactive TH1 responses in transplant models [18 ]. Undoubtedly, the best experiments to address these questions would involve using IL23 p19-/- mice, but they are currently unavailable. The other approach in evaluating the role of IL-23 in infectious and inflammatory models is to investigate changes in the phenotype of IL-12 p40-/- mice when IL-23 is replaced exogenously. In this regard, exogenous IL-23 has been reported to enhance resistance to T. gondii in one preliminary study [38 ].


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DOES IL-23 HAVE A DOWN-REGULATORY ROLE IN IMMUNE RESPONSES?
 
The signal-transduction pathways of IL-12 and IL-23 are very similar, but they differ in the extent to which they result in the activation of Stat4. Stat4 phosphorylation is less in response to IL-23 than IL-12 [8 , 9 ]. Although the significance of this difference has not yet been determined, it is conceivable that in certain circumstances where IL-12 and IL-23 are competing for shared receptor and signal-transduction components, IL-23 could act to down-regulate Stat4-dependent actions of IL-12. Supporting this possibility, data from experiments involving a murine model of hapten-induced colitis indicate that IL-12 p40 may act to diminish inflammation [24 ]. In this study, p40-/- mice developed more severe colitis even compared with wild-type mice. In contrast, IL-12 p35-/- mice had less severe colitis than wild-type or p40-/- mice [24]. Although it is possible that the IL-12 p40 homodimer may function to down-regulate inflammation in this model, the intriguing possibility that IL-23 may have this inhibitory function remains to be explored.


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IL-27: THE NEWEST MEMBER OF THE IL-12/23 FAMILY
 
Adding to the rapid developments in the understanding of the IL-12/23 family is the very recent report of a heterodimeric cytokine (termed IL-27) that now joins the family. Its subunits, Epstein-Barr virus-induced gene 3 and p28, have homology with IL-12/IL-23 p40 and IL-12 p35, respectively [39 ]. The receptor for IL-27 [39 ] (also termed TCCR or WSX-1) has homology with IL-12Rß2 [40 41 42 ]. IL-27 drives proliferation of naïve CD4+ T cells, similar to IL-12. It will be important to determine how IL-27 integrates into the IL-12/IL-23 cytokine family with regard to its function in CD4+ T cell activation and differentiation and to compare its signal-transduction characteristics with those of IL-12 and IL-23.


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IL-23: THE IMPORTANT REMAINING QUESTIONS
 
The recent discovery of IL-23 has provided a potential solution to some confusing contradictions that had arisen in studies of mice deficient in the components of IL-12. We now know that the IL-12 p40 subunit is shared between IL-12 and IL-23, explaining why the phenotype of IL-12 p40-/- mice is distinct and often more severe than that of IL-12 p35-/- mice (Table 1) . We also know that IL-23 and its receptor are expressed by different cells under different stimulation conditions than are IL-12 and its receptor. Although IL-12 and IL-23 share many similar actions (e.g., enhancing cellular proliferation, inducing IFN-{gamma} production, promoting TH1 costimulation by DC), these differences in expression patterns indicate a unique role for IL-23 in promoting cellular immune responses (Fig. 2 ). Certain time periods during immune responses may be dominated by IL-23-centered immune regulation. For example, whereas IL-12 acts on naïve CD4+ T cells, IL-23 preferentially acts on T cells that have been exposed to antigen, suggesting that it may function to sustain long-term cellular immune responses. This action of IL-23 to promote sustained T cell responses is critical, as experiments comparing IL-12 p35-/- and p40-/- mice indicate an essential role for IL-23 in clearing persistent intracellular infections [23 ], distinct from IL-12.



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  		Figure 2. IL-23 acts on memory CD4+ T cells and DC. IL-23 stimulation leads to IFN-{gamma} production and proliferative response in memory but not naïve CD4+ T cells. IL-23 differs from IL-12, which acts on naïve cells but has negligible effects on murine memory cells. IL-23 and IL-12 share a similar function in promoting TH1 costimulation by inducing IL-12 and IFN-{gamma} production by DC. MHCII, major histocompatibility complex class II.

Although the discovery of IL-23 addressed several prior mysteries, it will undoubtedly drive further investigation into questions that now arise. To what extent do other cytokines synergize with IL-23 (e.g., IL-2 and IL-18)? Is Stat4 required for the action of IL-23? Does exogenous IL-23 enhance resistance to intracellular infections in wild-type and/or p40-/- mice? Does IL-23 compete with IL-12 for receptor and signal-transduction components, and is this relevant? Is the IL-12/IL-23 p40 subunit shared with other cytokines? These questions can be addressed with the scientific tools that are available presently.

Other questions will be best answered using IL-23 p19-/- and/or IL-23R-/- mice and not indirectly in IL-12 p40-/- mice, which are essentially deficient in IL-12 and IL-23. How does the phenotype of IL-23 p19-/- mice compare with that of IL-12p40-/- mice, especially in mouse models of infection and inflammation? Is IL-23 p19 required for the normal function and survival of memory CD4+ T cells? Is IL-23 only proinflammatory, or are there circumstances where IL-23 is required to down-regulate immune responses? We anticipate the answers to these intriguing questions will come very soon.


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ACKNOWLEDGEMENTS
 
The authors thank Drs. John O’Shea, Massimo Gadina, and Ruth Cordoba-Rodriguez for their thoughtful comments and advice during the preparation of this manuscript.

Received June 28, 2002; accepted July 30, 2002.


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