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* Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, and
Institute of Immunology, University of Vienna Medical School, Vienna International Research Cooperation Center, Vienna, Austria;
Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 29892;
DNAX Research Institute, Palo Alto, CA 94304; and
¶ Harvard Skin Disease Research Center, Boston, MA 02115
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-2 (T1 cells) (5, 6). Structurally, IL-12 is a heterodimeric cytokine consisting of two disulfide-bonded chains, p35 and p40. Both subunits expressed by one cell are required for IL-12 bioactivity (6, 7). Recently, a novel four-
helix moiety, p19, that is very closely related in structure to the p35 subunit, has been described. Similar to p35, it has no biological activity by itself, but can form a disulfide-bonded heterodimer with p40 that is termed IL-23 (p19/40) (8). Whereas the biological activities of IL-12 (p35/40) are mediated by the high-affinity IL-12R, consisting of a 
1 and a 2 chain (9), IL-23 (p19/40) binds to IL-12R 1, but fails to engage IL-12R 2 (8).
Similar to IL-12, IL-23 is produced mainly by activated murine and human dendritic cells (8). Both cytokines induce IFN- production and proliferation of human PHA T cell blasts (5, 6, 8), but only IL-23 strongly augments the proliferation of mouse and human memory T cells (8).
The importance of IL-12 in vivo has been demonstrated using anti-p40 blocking Abs, which suppress T1-associated autoimmune responses such as experimental allergic encephalomyelitis and inflammatory bowel disease (10, 11, 12). In cutaneous immunity a pivotal role of IL-12 in the induction phase of contact hypersensitivity was demonstrated in blocking experiments using an anti-p40 Ab. This resulted in inhibition of sensitization and induction of hapten-specific tolerance (13, 14). One must assume that the anti-p40 Abs used in these studies have blocked the activity of not only IL-12 (p35/40), but also IL-23 (p19/40). Thus, the specific contributions of IL-12 and IL-23 to the immunopathology of T1-associated immunity remained unclear.
Using our recently generated keratin 14 (K14)/p40 transgenic (TG) mice, we demonstrate constitutive production of IL-23 (p19/p40), but not IL-12 (p35/40) (15), in the basal layer of the epidermis, allowing us to study the effects of IL-23 on cutaneous immunity. Our results revealed that p40 TG mice exhibit an increased number of Langerhans cells (LC) with a more mature phenotype when compared with littermate (LM) controls. Upon s.c. injection of IL-23, non-TG LM develop an inflammatory response comparable to that of K14/p40 mice. In an allogeneic skin transplantation model, the accelerated rejection of K14/p40 skin speaks for an important in vivo role of IL-23 in T1-mediated immunity.
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Materials and Methods |
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IL-12 p40 TG mice were generated by cDNA injection into fertilized ova as previously described (15). Using the keratin-14 (K14) promoter, transgene expression was targeted to the basal layer of the epidermis. Two heterozygous mouse lines designated K14/p40.1 and K14/p40.10 were obtained. All animals were bred under pathogen-free conditions. For transplantation experiments, female mice of equivalent age (6–10 wk) were used. These included K14/p40 and LM mice, both on a FVB background (H-2q), and BALB/c mice (H-2d). Each experimental and control group consisted of four to five animals.
Epidermal cell culture and IL-23 ELISA
Epidermal cell suspensions (ECS) were obtained by sequential dispase and trypsin digestion of split mouse ears as previously described (16). KC thus obtained were cultured on collagen-coated plates using nondifferentiating conditions with medium containing 0.05 mM Ca2+ to allow maintenance of K14 expression. After 48 h of culture, cells were used for RT-PCR, and immunoreactive IL-23 secreted into the supernatant was quantified by an ELISA selectively detecting IL-23 (p19/p40) and not p40 or IL-12 (p35/40), according to the procedure previously described (8).
RNA analysis and sequencing
For RT-PCR, total RNA was prepared from cultured basal TG and control KC using the RNEASy Minikit from Qiagen (Valencia, CA). An amount of 1 µg of total RNA was reverse transcribed using the Superscript First Strand Synthesis System for RT-PCR from Life Technologies (Gaithersburg, MD). Two microliters of the RT reaction were amplified using primers specific for murine p19, murine p40, and -actin. For the -actin primers, published sequences were used (17). For PCR amplification, 50 µl of the reaction mixture containing 1 µl cDNA, 200 mM dNTP (each), 20 pmol of each primer, standard buffer supplemented with platinum Taq polymerase (2.5 U/reaction; Life Technologies), and 1.5 mM MgCl2+ was used. Primer sequences and product sizes were as follows: p19 sense, 5'-GGGAACAAGATGCTGGATT-3', p19 antisense, 5'-CTTCACACTGGATACGGGG-3', 215 bp; -actin sense, 5'-GTCGTACCACAGGCATTGTGATTG-3', -actin antisense, 5'-GCAATGCCTGGGTACATGGTGG-3', 490 bp; p40 sense, 5'-AGATGACATCACCTGGACCT-3', p40 antisense, 5'-GCCATGAGCACGTGAACCGT-3', 260 bp. Samples were amplified in a thermal cycler (PerkinElmer, Foster City, CA) with an initial 3-min denaturation step followed by 35 cycles at 94, 56, and 72°C, all for 1 min. PCR products were separated at 120 V in a 1.5% agarose gel. Amplification of -actin verified the presence of cDNA. For sequencing of the TG and LM KC PCR product, the 215-bp gel bands were excised and cloned into the CR2.1 vector using the Topo 10 kit (Invitrogen, San Diego, CA). Two clones derived from both the TG and the LM KC product were sequenced using the p19 upper primer described previously. PCR products were analyzed by dye terminator cycle sequencing (ABI-PRISM; PE Biosystems, Warrington, U.K.) on an ABI PRISM 373A DNA sequencer (PE Biosystems) following the manufacturer’s instructions.
Subcutaneous injection of IL-23
LM mice (five per group) were injected s.c. into the right ear with either IL-23 (100 ng) or vehicle (PBS + 1% BSA) in a total volume of 50 µl every other day for 10 days. Ear thickness was measured before and at multiple time points after injection with an engineers’s caliper (Hahn and Kolb, Stuttgart, Germany). On day 10, ECS were prepared by sequential dispase and trypsin treatment. Cells were then incubated with FITC-conjugated 30F11.1 (anti-CD45; BD PharMingen, San Diego, CA) and PE-conjugated M5/114.15.2 (anti-I-Ab,d,q and I-Ed,k; Boehringer Mannheim, Vienna, Austria) and subjected to two-color flow cytometric analyses.
Epidermal cell suspension and FACS sorting of LC and KC
Freshly isolated or 3-day cultured ECS was stained with the FITC-conjugated anti-CD45 and the PE-conjugated 145-2C11 (anti-CD3; BD PharMingen) mAbs and sorted using the FACS Vantage flow cytometer (BD Biosciences, San Jose, CA). The gate for sorting the LC subset was set on the CD45+/CD3- population. Depending on the sample, 2–9% of all epidermal cells were recovered with a purity of >95% as confirmed by reanalysis of sorted populations. KC were sorted from the CD45-/CD3- fraction (85–95% of all epidermal cells) with a purity of 99%.
Skin organ cultures and epidermal sheet cultures
Mouse ears were split into ventral and dorsal halves. Dorsal ear halves were floated dermal side down on normal culture medium (RPMI 1640 supplemented with 10% heat-inactivated FCS, 1x antibiotic/antimycotic, 25 mM HEPES, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 2 mM L-glutamine, 5 x 10-5 2-ME; Life Technologies). Epidermal sheets were prepared by ammonium thiocyanate treatment from dorsal halves of freshly separated ears and at selected time points after culture in normal culture medium. Epidermal LC were stained with mAbs against MHC class II and DEC 205 (NLDC-145). The density of LC was counted under the microscope at x400 magnification using a calibrated grid. Four sheets per experimental group were evaluated. The number of LC in 80 randomly chosen grids was determined and expressed as the number of cells (±SD) per square millimeters of skin. Areas with hair follicles were not analyzed.
In addition, epidermal sheets were prepared by dispase treatment of split mouse ears (16) and placed in normal culture medium. The total number of cells emigrating out of the sheets and the number of LC, identified by their veiled appearance, were counted under the hemocytometer at the time points indicated. In addition, flow cytometric analysis of nonadherent migratory cells was performed. LC were assessed using either the biotinylated mAb N418 (anti-CD11c) or the FITC-conjugated anti-CD45 together with PE-conjugated M5/114.15.2. Data are presented as the mean number of LC/sheet ±SD of three experiments per group.
Two-color flow cytometry
ECS were prepared by sequential dispase and trypsin treatment (16) and subjected to flow cytometric analysis. To prevent degradation of cadherin epitopes by trypsin in 1 mM EDTA, we used a modified digestion protocol (18) that uses trypsin in HBSS supplemented with 1 mM Ca2+ and 10 mM HEPES.
The exact phenotype of freshly isolated TG LC, LM LC, and 3-day cultured LC was characterized by two-color flow cytometry using the biotinylated mAb N418 as a LC marker and the FITC-conjugated mAbs 16-10A1 (anti-CD80), GL1 (anti-CD86), 3E2 (anti-CD54), IM7.8.1 (anti-CD44), 7D4 (anti-CD25), 30-F11 (anti-CD45), M1/69 (anti-CD24), all purchased from BD PharMingen. Tissue culture supernatant of the hybridoma NLDC-145 was obtained from Serotec (Oxford, U.K.). Hybridomas M5/114.15.2 and F4/80 (macrophage) were obtained from American Type Culture Collection (Manassas, VA). ECCD-2 (anti-E-cadherin) was purchased from Zymed Laboratories (San Francisco, CA), and the 28-14-8 mAb (anti-mouse H-2Db, cross-reactivity with H-2Dq) was purchased from Southern Biotechnology Associates (Birmingham, AL). Some of the mAbs used were purified from supernatants of the corresponding hybridomas. Before FITC or biotin conjugation, protein concentrations were adjusted to 1 mg/ml.
Control stainings were performed with isotype-matched control Abs (BD PharMingen). Dead cells were identified by 7-amino-actinomycin D uptake and excluded from the analysis. Samples were analyzed on a FACScan (BD Biosciences).
T cell proliferation assay
Naive T cells from BALB/c mice were prepared as described elsewhere (19). T cells (responders, 1 x 105/well) were cultured in 96-well round-bottom culture plates (Costar, Cambridge, MA) with sorted LC or KC from either fresh or 3-day cultured LM and K14/p40 ECS (stimulators, 5 x 102–0.5 x 10 cells/well). Proliferative responses were measured on days 3, 4, and 5 by uptake of [3H]thymidine (Amersham, Arlington Heights, IL) added during the final 12 h of culture.
Skin graft experiments
Skin grafting was performed according to the method described by Lenz et al. (20). Before harvesting full thickness skin grafts (1 x 1 cm) from the thoracic wall, donor mice were sacrificed by cervical dislocation, and the truncal skin was shaved. Recipient mice were anesthetized with Xylanest (Bayer, Elkhart, IN) and Rompun (Parke Davis, Mumbai, India). Following removal of the skin down to the panniculus carnosus, skin grafts were transplanted onto graft beds on the shaved right thoracic wall of recipient mice. The grafts were clamped by metallic clips (autoclip 9 mm; Clay Adams, Parsipanny, NJ), which were removed a week after skin grafting. Skin grafts were inspected daily by two blinded investigators starting 7 days after transplantation. Rejection was judged to be complete when the entire graft appeared hard and avascular. Results are expressed as mean survival time (MST) of the grafts.
Statistical analysis
Data from T cell proliferation assays are expressed as mean cpm ± SEM. For the skin graft experiments, experimental groups consisted of four to five mice. Experiments were performed twice. Comparison of the MST of skin grafts between groups was calculated by the Mann-Whitney U test. A p value of 
0.05 was considered to be significant.
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Results |
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We have previously shown high level p40 transgene expression in K14/p40 mice. TG KC secreted p40 and p40/40 but no heterodimeric IL-12 (15). To investigate whether basal KC produce endogenous p19, which has previously been described to pair with IL-12 p40 to form IL-23, RT-PCR for p40 and p19 was performed. P19 mRNA was expressed in both LM and TG basal KC, whereas p40 mRNA was detectable only in KC from TG mice (Fig. 1). Sequencing of the 215-bp PCR product confirmed the identity of p19 in both basal TG and LM KC (data not shown). To ascertain that p19 and p40 mRNA expression in TG KC results in IL-23 protein secretion, a specific ELISA for mouse IL-23 was performed. Medium conditioned by TG KC contained 2.99 ng/ml and 1.25 ng/ml IL-23 in the two TG lines K14/p40.1 and K14/p40.10, respectively (Table I). Considering a total p40 immunoreactivity of 32 ng/ml in p40.1 and 8.04 ng/ml in p40.10 mice (15), IL-23 comprised 8.2% of this amount in K14/p40.1 and 8.9% in K14/p40.10. No IL-23 could be detected in supernatants conditioned by LM KC and in plasma from TG and LM mice (Table I).
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p40 TG mice spontaneously develop an inflammatory skin phenotype, which is reflected by increased ear thickness, higher numbers of LC, and up-regulation of MHC class II expression on KC when compared with non-TG LM (15). To determine whether IL-23 is responsible for the inflammatory changes seen in K14/p40 mice, we s.c. injected rIL-23 or vehicle alone every other day in the ears of non-TG LM for a period of 10 days. Similar to the spontaneous ear-thickening in K14/p40 mice, we observed an ear-swelling response up to 126 µm ± 32 on day 10 after repeated injections of rIL-23, but not vehicle (Fig. 2A). Flow cytometric stainings revealed a higher content of epidermal LC (8.8%) and up-regulation of MHC class II on KC in mice receiving IL-23 injections as compared with vehicle recipients and uninjected LM with 2.5 and 2.3% LC, respectively (Fig. 2B). Identical cellular characteristics were observed in K14/p40 mice (Fig. 2B). As previously shown by Kopp et al. (15), a comparable skin phenotype can be induced by s.c. injections of rIL-12, indicating that IL-12 and IL-23 exert overlapping in vivo properties.
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Our previous results showing increased numbers of LC in p40 TG skin when compared with LM skin initiated a more detailed investigation of the number, the phenotype, and the migratory capacity of these cells. Immunohistochemical stainings of epidermal sheets using the mAbs M5/114.15.2 and NLDC-145 revealed a 2-fold higher density of LC in epidermal sheets from TG mice when compared with LM. During culture, a comparable reduction of the number of LC residing in TG and LM epidermis was observed reaching 89% and 82% at 72 h, respectively (Fig. 3A).
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Examination of phenotypic characteristics of K14/p40 LC
The phenotypic characteristics of LC in single-cell suspensions prepared from TG and LM ear skin were determined by microscopy and flow cytometry. Cells with dendritic morphology were noted in freshly prepared ECS from TG mice, but not from LM, suggesting advanced maturity of K14/p40-derived LC. Flow cytometric analysis of freshly isolated LM ECS revealed the typical features of immature LC, i.e., a lack of CD80, CD86, and CD40; low levels of CD54 and CD44; moderate levels of CD45, MHC class I and II, and F4/80; and high levels of E-cadherin and CD24 (Fig. 4A). In contrast, freshly isolated LC from TG mice exhibited measurable levels of CD80, CD86, and CD40 and moderate levels of CD54 and CD44. The levels of F4/80 and MHC class II were comparable in both LM- and K14/p40-derived LC, whereas E-cadherin was expressed slightly less in freshly isolated LC from p40 TG mice (Fig. 4B). After 3 days of culture, both LC from LM mice (Fig. 4C) and TG mice (Fig. 4D) showed features of maturity with a slightly stronger increase in expression of MHC class II and the costimulatory molecules CD80, CD86, and CD54 in p40 TG-derived LC (Fig. 4D). These data indicate that TG skin contains an LC population that has already started phenotypic metamorphosis toward maturity and that upon 3-day culture, TG LC sustain their maturational lead.
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The next set of experiments was designed to investigate the capacity of LC from p40 TG mice to stimulate primary T cell responses. LC were isolated from fresh LM, fresh TG, and 3-day cultured LM and TG ECS by anti-CD45/anti-CD3 sorting as described in Materials and Methods. The ability of these LC populations to stimulate allogeneic T cells was investigated in mixed lymphocyte reactions. Three-day cultured LM LC expectedly acted as excellent stimulators of allogeneic T cells (Fig. 5A). Nevertheless, 3-day cultured LC from TG mice exceeded them in their stimulatory capacity (Fig. 5A). In contrast to freshly isolated LM LC, which essentially lacked any stimulatory potential, freshly isolated LC from TG mice induced a pronounced proliferative response in allogeneic T cells (Fig. 5B). The T cell reaction elicited by freshly isolated LC from p40 TG mice was approximately half of that induced by fully matured LM LC. Although these experiments suggested that freshly isolated LC from TG mice are effective stimulators of allogeneic T cells, the possibility that MHC class II+/CD54+ KC "contaminating" the LC population would contribute to, or even be responsible for, this reaction could not be definitively excluded. To address this issue, we used purified KC as MLR stimulator cells and found that, in sharp contrast to LC freshly isolated from TG mice, neither TG nor LM KC were able to induce significant allogeneic T cell proliferation (Fig. 5C). These observations point to the critical involvement of K14/p40-derived LC, but not KC, for productive alloantigen presentation.
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Accelerated rejection of skin grafts from p40 TG mice
To investigate the effect of IL-23-dependent numeric and phenotypic alterations in the LC population on allogeneic immune responses in vivo, cutaneous transplantation experiments were performed. Full thickness skin grafts from either LM or K14/p40 (both H-2q background) mice were obtained and transplanted onto graft beds of BALB/c recipients (H-2d) across a full MHC class I and class II disparity. Rejection was evaluated on a daily basis starting 7 days after transplantation and was judged to be complete when the entire graft appeared hard and avascular. Skin graft rejection was significantly accelerated in mice receiving skin grafts from K14/p40 donors when compared with recipients of LM skin grafts (MST = 8.8 ± 0.67 days vs 10.7 ± 0.29 days) (Table II). These data indicate increased immunogenicity of TG skin. In the reverse setting where skin grafts from BALB/c mice were transplanted onto K14/p40 mice and LM controls, we did not observe a significant difference in the rejection pattern of grafts in K14/p40 vs LM recipients.
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Discussion |
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8–9% of total p40 immunoreactivity, predominates over the antagonistic effects of p40 and p40/40 secreted in K14/p40 mice. The similarity between the skin phenotype induced by IL-23 (this study) and, as previously shown, IL-12 (injections of IL-12 in LM mice) (15) speaks for overlapping in vivo functional properties of IL-23 and IL-12. We also show that p40 TG mice exhibit increased numbers of LC with a more mature phenotype when compared with LM controls, and that this correlates with the increased alloimmunogenicity of K14/p40 skin.
It is very unlikely that the observed effects are because of p40, p40/40, or minute amounts of IL-12 (p35/40) escaping our detection because of the following. 1) Injections of recombinant p40 and p40/40 into the skin of LM mice failed to induce skin inflammation (15). Instead, p40/40 inhibited IL-12-dependent IFN- secretion by splenocytes (15), which is consistent with the observation that p40 homodimers can function as IL-12 antagonists (21, 22, 23). 2) As far as heterodimeric IL-12 is concerned, we were not able to detect p35 mRNA expression and/or IL-12 protein secretion by TG KC, nor could we find IL-12-induced IFN- secretion in an IL-12 bioassay (15). Therefore, we feel that IL-23 is the most likely explanation for the changes observed in the skin of p40 TG mice.
Our results demonstrating an in vivo proinflammatory function of IL-23 are in accordance with a study by Wiekowski et al. (24) showing that transgene expression of p19 in bone marrow-derived cells, which are able to produce p40, induces systemic inflammation, impaired growth, and premature death. The difference in the extent of the disease, with ubiquitous inflammation in p19 TG mice and only cutaneous inflammation in K14/p40 mice, may be linked to the distinct sites of transgene expression and/or different levels of IL-23 secretion. The proinflammatory potential of this cytokine is also supported by the observation that IL-23 is essential for the development of autoimmune inflammation of the brain (25). The absence of cutaneous inflammation in LM mice expressing p19 alone is in accordance with the observations that p19 by itself lacks biological activity (8) and that TG overexpression of p19 in liver cells, which are unable to produce p40, does not induce an inflammatory phenotype (24). The expression of p19 by LM KC in the absence of p40 is not unusual, because p35 is also expressed more widely than p40. However, in the end it is the induction of p40, which determines the ability of a cell to secrete biologically active IL-12 (p35/40) and/or IL-23 (p19/40) (8).
Because of the preeminent importance of LC in skin-induced immune responses (20, 26, 27, 28, 29), we were interested in the effects of the TG products (p40, p40/40 and IL-23) on this cell population. Freshly isolated epidermal cells from TG mice contained LC with phenotypic and functional characteristics of an "intermediately mature" stage, whereas LC in LM mice were immature. These findings are in accordance with observations by Belladonna et al. (30) that IL-23 exposure of splenic DC allows for an immunogenic presentation of an otherwise tolerogenic tumor peptide. When cultured for 3 days LC from TG mice kept their maturational lead as determined by their enhanced expression of costimulatory molecules and increased allostimulatory capacity. Optimal sensitization to skin transplants requires good migratory abilities of LC to access draining lymph nodes and to sensitize host T cells to the alloantigens (31, 32, 33). Our epidermal sheet cultures addressing this issue revealed a higher LC density in TG skin when compared with LM skin and comparable migratory abilities and kinetics of LC from both TG and LM animals. These results imply that IL-23 disturbs the balance within the cutaneous immune system by the induction of quantitative and qualitative changes in the LC population, preparing skin to perform enhanced immune responses.
Transplantation studies showed that skin grafts from K14/p40 donors were rejected by allogeneic recipients in an accelerated fashion. This phenomenon may be due to: 1) enhanced priming of recipient T cells by higher numbers of skin-derived DC with increased allostimulatory capacity or 2) an enhanced stimulation of allogeneic T cells at the effector site driven by the proinflammatory milieu present in the p40 TG graft. We did not observe a difference in the rejection pattern of skin grafts from BALB/c donors transplanted on either p40 TG or LM recipients. Considering these results, the enhanced priming of recipient T cells by LC from TG grafts and not the "proinflammatory milieu" at the site of the graft is the most likely explanation for accelerated rejection of allogeneic K14/p40 skin grafts. The investigation of second set reactions in previously immunized mice will clarify this issue. The theoretical possibility of a systemic effect induced by IL-23, either secreted by KC within the TG graft in BALB/c recipients or by KC from TG recipients receiving BALB/c grafts, is highly unlikely as we failed to detect IL-23 in the plasma of the recipients (data not shown).
p40 and p40/40, which are also secreted by K14/p40 mice, are unlikely to contribute to the accelerated allograft rejection of TG skin, given that these molecules are not able to provoke the same phenotype as observed in K14/p40 mice (15) upon injections and because p40/40 delays but does not accelerate allograft rejection (34, 35, 36). It is conceivable that competitive binding of p40/40 to the IL-12R1 not only antagonizes IL-12- but also IL-23-mediated effects. However, as the antagonistic activity of p40 and p40/40 is overruled by the proinflammatory function of IL-23, this is unlikely to occur in K14/p40 mice.
The mechanism by which TG IL-23 induces activation of KC, accumulation and differentiation of LC, and ultimately accelerated allograft rejection remains to be determined. Both direct and indirect effects (e.g., via the secretion of proinflammatory cytokines by TG KC) of this cytokine are conceivable (15). The identification of IL-23R, composed of IL-12R1 (the p40-specific component of the IL-12R) and the novel cytokine receptor subunit IL-23R (8, 37) on mouse bone marrow macrophages, mouse dendritic cells, human and mouse memory T cells, and human NK cells, opens the possibility that in addition to its effects on LC, IL-23 secreted by TG skin grafts enhances rejection by further activation of alloreactive memory T cells at the site of the graft.
In summary, our data provide evidence that IL-23 regulates the induction of cutaneous immune responses toward increased immunogenicity. It would not be surprising to find this molecule abnormally expressed in T cell-mediated skin disorders, and it could become an interesting pharmacological target in conditions such as psoriasis, allergic contact dermatitis, and atopic dermatitis.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: KC, keratinocyte; K14, keratin 14; LC, Langerhans cell; MST, mean survival time, ECS, epidermal cell suspensions; LM, littermate; TG, transgenic.
Received for publication November 27, 2002. Accepted for publication March 25, 2003.
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References |
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production by T helper 1 cells. Eur. J. Immunol. 26:659.[Medline]
-type cytokine receptor subunits. Proc. Natl. Acad. Sci. USA 93:14002.-actin mRNA. Nucleic Acids Res. 14:289.
1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168:5699.Related articles in The JI:
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