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Cutting Edge: Polymorphisms in the ICOS Promoter Region Are Associated with Allergic Sensitization and Th2 Cytokine Production ¹

Rebecca A. Shilling^2,*, Jayant M. Pinto^2,,, Donna C. Decker^*, Daniel H. Schneider, Hozefa S. Bandukwala, Jeffrey R. Schneider^*, Blanca Camoretti-Mercado^*, Carole Ober and Anne I. Sperling^3,*,

^* Section of Pulmonary and Critical Care Medicine, Department of Medicine, Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, Department of Human Genetics, and Committee on Immunology, The University of Chicago, Chicago, IL 60637

	Abstract

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The establishment of ICOS as an important regulator of Th2 development and effector function makes the ICOS locus an attractive candidate for Th2-mediated diseases, such as asthma and allergy. In evaluation of this candidate locus in humans, we identified 11 variants and determined that two in the putative promoter region are significantly associated with allergic sensitization and serum IgE levels. In addition, cultures of activated PBMCs from individuals homozygous for the associated polymorphisms produced increased levels of the Th2 cytokines, IL-4, IL-5, and IL-13, as well as TNF- compared with controls. One of the polymorphisms, –1413G/A, demonstrated differential NF-B binding in mobility shift analysis, suggesting that this polymorphism has functional consequences. Overall, these data demonstrate that ICOS is a susceptibility gene for allergic sensitization, perhaps through the promotion of Th2 differentiation.

	Introduction

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The ICOS molecule, a member of the CD28 family, is an important regulator of T lymphocyte function and differentiation (1, 2). Although its ligand, B7RP-1, is expressed constitutively on B cells, dendritic cells, and macrophages, ICOS is T cell specific and induced after activation (2). We and others have found that in vivo ICOS blockade attenuates Th2-mediated pulmonary inflammation in murine models of allergic asthma and reduces Th2 effector cytokine production ex vivo (3, 4, 5). Furthermore, ICOS^–/– mice have been shown to have markedly reduced levels of IgE, and ICOS^–/– T cells produce lower levels of IL-4 compared with wild-type T cells (6, 7, 8). Although ICOS has also been shown to be important in Th1-mediated disease models, the literature establishes ICOS as an important regulator of Th2 immune responses (2).

Asthma and allergy are the most common chronic Th2-mediated diseases, affecting millions of people worldwide. ICOS and other members of the CD28 family are located on chromosome 2q33-4, a region that has been linked with asthma, allergy, and related phenotypes in several genome-wide scans (9). Other investigators have studied polymorphisms in the human ICOS gene, but none have examined associations with allergy or conducted functional studies of the variants (10, 11, 12, 13, 14). In our study, we surveyed the ICOS gene for variation and identified polymorphisms in the promoter region that are associated with increased Th2 cytokine production, allergic sensitization, and total serum IgE levels.

	Materials and Methods

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Identification of genomic structure and polymorphism detection

To detect polymorphisms in the ICOS gene, 30 DNA samples were selected without regard to disease status from 10 Hutterites (described below; Ref. 15), 10 unrelated European Americans, and 10 unrelated African Americans. ICOS PCR products were analyzed by denaturing HPLC (Varian Chromatography Systems), and variant denaturing HPLC patterns were sequenced on an ABI 3700 sequencer using the BigDye Terminator technology (Applied Biosystems). Approval from The University of Chicago Institutional Review Board was obtained for these studies.

Genotyping and association studies

To test for associations with asthma and atopy, we studied 750 members of a 13-generation, 1623-person Hutterite pedigree who were previously evaluated for atopy by skin prick tests (SPTs) ⁴ to 14 airborne allergens and measurements of total serum IgE, and for asthma and bronchial hyperresponsiveness to methacholine (15). The Hutterites are a founder population of European origin who now reside in North America; >35,000 Hutterites are descendants of 64 ancestors. Additional details on the Hutterite population are provided elsewhere (15). Selected single nucleotide polymorphisms (SNPs) in ICOS were genotyped in these individuals using standard methods (15, 16). To test for differences in genotype frequencies between Hutterite cases and controls, we used an association test that takes into account the relatedness between individuals (17); to test for associations with the quantitative trait, mean (ln) IgE, we used a general two-allele model test that also takes into account the relatedness between Hutterites (18).

EMSA

Nuclear extractions were prepared using a standard protocol (19). Double-stranded oligonucleotide probes were generated by annealing complementary synthetic oligonucleotides and end-labeling with T4 polynucleotide kinase (New England Biolabs) and [-³²P] ATP (Amersham Biosciences). The nuclear extract (5 µg) was incubated with 3000 cpm of labeled probe and 1 µg of poly(dI-dC). For the competition assays, 100- to 200-fold molar excess of unlabeled oligonucleotide was added. Abs used for supershifts included the following: GATA-3, NF-B p50, NF-B p52, c-rel (sc-268x, sc-7178x, sc-7386x, sc-6955x; Santa Cruz Biotechnology), and NF-B p65 (gift from Dr. G. Franzoso, University of Chicago, Chicago, IL, and Roche Applied Science, Indianapolis, IN).

Cell preparation and analysis

PBMCs were obtained from individuals within the Chicago community who were homozygous for either the –1413A/–693A or the –1413G/–693G haplotype. Cells were analyzed by flow cytometry with anti-CD4, CD8, CD69, CD28 (BD Biosciences), and anti-ICOS (eBiosciences). PBMCs were stimulated on anti-CD3 (OKT3; 1 µg/ml)-coated plates, and after 48 h, the cell culture supernatants were tested for cytokine content by a cytometric bead array (BD Biosciences). IL-13 was measured by ELISA (R&D Systems). Significance was determined using the unpaired Student’s t test.

	Results

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SNPs in the 5' region of ICOS are associated with allergic sensitization and serum IgE

We identified 11 variants that partially overlap with previously reported polymorphisms (10, 11, 12, 13): three SNPs in the 5' flanking sequence (–1413G/A, –868T/A, and –693G/A), one synonymous SNP in exon 2 (Q50Q; 18915A/G), one SNP in intron 3 (20873C/T), one SNP in intron 4 (22749T/G), four SNPs in the 3' untranslated region (22790A/C, 23752T/C, 23925C/T, and 24195G/A), and a dinucleotide repeat polymorphism in intron 4 (22643GT_8–14).

Members of the Hutterite pedigree were genotyped for four SNPs (–1413, –693, 23752, and 24195). The –868 SNP was not present in the 10 Hutterites in the screening set and was therefore not typed in the larger sample. There was no association between any of the phenotypes and the two SNPs in the 3' untranslated region (p > 0.10). However, the –1413A and –693A alleles were significantly associated with allergic sensitization to airborne allergens (more than one positive SPT), and the –693AA and –1413AA genotypes were associated with increased total serum IgE levels (adjusted for age and gender) (Table I). These two SNPs are in linkage disequilibrium (LD), so the results are nearly identical. In particular, allergic sensitization to pollens, house dust mite, and cockroach allergens was more common among Hutterites with the –1413A and –693A alleles (Table I), and the prevalence is markedly increased in individuals homozygous for these SNPs (Fig. 1). Moreover, the mean (ln) IgE values were 4.13 (SD, 1.51) among AA, 3.23 (SD, 1.67) among GA, and 2.94 (SD, 1.60) among GG individuals (p = 0.0014). Although we did not find an association with asthma or bronchial hyperresponsiveness in this population (p > 0.10), it should be noted that the Hutterites are farmers and generally have mild asthma that infrequently requires inhaled corticosteroids or hospitalizations. Because the prevalence of atopy (more than one positive SPT) among Hutterite asthmatics is only 50%, compared with outbred populations in which >70% of asthmatics are atopic (15), allergic sensitization may not be a risk factor for asthma in the Hutterites, as it is in other populations. Nonetheless, our data show that one or both promoter SNPs, or other polymorphisms that are in LD with the –1413 and –693 SNPs, are associated with an increased risk for atopic responses to common airborne allergens and IgE production in this population.

View larger version (25K): [in this window] [in a new window]   FIGURE 1. Prevalence of allergen sensitization is increased in –1413AA/–693AA individuals. The prevalence of allergen sensitization to any allergens (1+ SPT) or to cockroaches (CR+ SPT) is increased for the genotype –1413AA/–693AA (AA) compared with either –1413GA/–693GA (GA) or –1413GG/–693GG (GG).

The –1413G allele represents an NF-B p50 binding site

Using the TRANSFAC 4.0 database, we found that the –1413G allele contained a site that is 90% homologous to the consensus NF-B p50 binding site, whereas the –1413A allele eliminated the homology. To test whether the –1413 SNP was within an NF-B site, two 24-mer probes, identical except for the –1413 SNP, were used in EMSA analysis. The –1413G probe, but not the –1413A probe, bound nuclear proteins in a pattern identical to an NF-B consensus probe using both CEM and HeLa nuclear lysates (Fig. 2, a and b). The unlabeled –1413A oligonucleotide failed to compete for protein binding to either the –1413G or consensus NF-B probes, whereas the unlabeled –1413G and NF-B oligonucleotides eliminated protein binding to the –1413G probe (Fig. 2a). Abs to both p50 and p65 subunits supershifted the –1413G bands in HeLa cells, suggesting that p50-p65 heterodimers were bound (Fig. 2b). In CEM cells, anti-p50 Ab supershifted the entire –1413G band, but only a partial shift occurred with anti-p65 Ab, suggesting that predominantly p50 homodimers were binding (Fig. 2c). Anti-p52, anti-c-rel, and the control Abs had no effect. EMSA analysis of the –693 SNP did not reveal a difference in nuclear protein binding between the two alleles, and unlabeled oligonucleotides blocked binding to self-probe as well as the converse allele (data not shown). Thus, although the –693 SNP does not represent a site for variation in transcription factor binding, the –1413G allele represents a p50 NF-B site that can bind p50 homodimers or p50-p65 heterodimers.

View larger version (72K): [in this window] [in a new window]   FIGURE 2. The –1413G probe binds p50 homodimers in a pattern identical to NF-B. A, The –1413G probe (lanes 6–10) bound nuclear proteins from CEM lystates in a pattern identical to an NF-B probe (lanes 11–15); binding was extinguished by an unlabeled self probe and NF-B probe (lanes 9, 10, 13, and 14). No distinct pattern was seen with the –1413A probe (lanes 1–5), and the –1413A probe could not block nuclear protein binding to the –1413G probe or the NF-B probe (lanes 7 and 12). B, Using HeLa nuclear extracts, the –1413G probe bound nuclear proteins in a pattern identical to an NF-B consensus probe (arrow; lanes 6 and 11). Both –1413G and NF-B DNA-protein complexes were supershifted with an anti-p50 Ab (*; lanes 7 and 12) and with an anti-p65 Ab (lanes 8 and 13). No shifts in the –1413G or NF-B bands were seen with the control Ab, anti-c-myc (lanes 9 and 14). Unlabeled NF-B oligonucleotide extinguished protein binding to –1413G (lane 10). The –1413A probe did not bind nuclear proteins with the same pattern as –1413G (lanes 1–5). C, The –1413G probe bound nuclear proteins with increased intensity with stimulated CEM nuclear lysates than with unstimulated (arrow). Anti-p50 Ab completely supershifted the band (*; lane 7), whereas only a partial shift was observed with an anti-p65 Ab (** lane 9). Anti-p52, anti-c-rel, and control Ab (anti-GATA-3) did not affect the position or intensity of the band (lanes 8, 10, and 11). NS, Nonspecific.

The association of the promoter region SNPs with atopic responses, together with differences in transcription factor binding, led us to examine whether the –1413 alleles were associated with differences in ICOS expression on T cells and cytokine production. Individuals were recruited in the Chicago area, and five homozygous –1413A individuals were identified. PBMCs from these individuals, as well as eight homozygous for the –1413G allele, were stained for ICOS expression and other T cell markers before and after activation. A small but significant difference in ICOS expression was found on CD4 and CD8 T cells between the –1413AA and –1413GG genotypes before activation (Fig. 3a). Although there was a trend toward increased ICOS expression on the –1413AA CD4⁺ T cells 2 and 7 days after stimulation, significance was not reached (Fig. 3b). Other markers, such as CD28 and CD69, did not show any significant differences between the genotypes before or after stimulation (data not shown). On day 2, supernatants from these cultures were analyzed for cytokines, and –1413AA cell cultures contained significantly higher levels of IL-4, IL-5, IL-13, and TNF- compared with cultures from –1413GG cells (Fig. 3c). No differences in IL-10, IL-2, and IFN- levels were seen. To determine whether these findings were reproducible, we tested all of the –1413AA and six of the eight –1413GG individuals a second time and found similar results (data not shown). Although we have no clinical information with regard to Th2-skewed diseases or autoimmunity in these volunteers, we saw no differences in the ratio of CD4:CD8 T cells (2:1) to suggest gross differences in lymphocyte populations.

View larger version (29K): [in this window] [in a new window]   FIGURE 3. Th2 cytokines are significantly increased in cultures of –1413AA PBMCs. A and B, ICOS expression is increased on CD4+ and CD8+ T cells from –1413AA individuals before in vitro activation (A) but is not significantly higher on days 2 and 7 after activation with anti-CD3 (B). C, Supernatants from PBMCs stimulated for 48 h with anti-CD3 were measured for cytokines by cytometric bead array or by ELISA (IL-13). Cultures of PBMCs from individuals homozygous for –1413A (filled bars) had increased levels of the Th2 cytokines, IL-13, IL-5, and IL-4, as well as TNF-, compared with cultures from individuals homozygous for –1413G (open bars). No significant differences in the Th1 cytokines, IFN-, and IL-2 were found, nor was there a significant difference in the amount of IL-10. Student’s t tests are shown (**, p < 0.01; *, p < 0.05; ns, not significant).

	Discussion

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Given that the subjects used in the cytokine experiments were chosen without regard to allergic phenotypes, it is remarkable that significant differences in cytokine production were found based solely on genotype at a single locus. The finding of increased TNF- is particularly interesting given its role as a proinflammatory cytokine that has been implicated in Th2 development in a murine system and in the pathogenesis of asthma in studies involving humans (21, 22). The mechanism by which the –1413 SNP affects ICOS expression and Th cytokine production may be explained by the potential differential transcription factor binding of NF-B. p50 homodimers have been shown previously to be negative regulators of transcription by several groups, and mutations at these sites actually leads to increased gene expression (23, 24, 25, 26). However, we must stress that it is possible that the –1413/693 SNPs are in LD with other polymorphisms and that it is these unknown polymorphisms that are responsible for the associated phenotypes described. Although additional studies are necessary to prove that NF-B plays a role in the transcriptional regulation of ICOS, our data support a model in which loss of NF-B regulation with the –1413AA genotype may increase ICOS expression on the cell surface and lead to changes in T cell differentiation and function.

The increase in Th2 cytokines in our system is likely attributable to secretion by memory T cells, because several groups have shown that it is predominantly memory, not naive, human T cells that produce IL-4 mRNA and protein at early time points (27). Because we also found increased levels of ICOS expression on –1413AA CD4⁺ and CD8⁺ T cells before activation, it is probable that increased ICOS expression is associated with an increased Th2 memory pool. Together, our data suggest that –1413AA individuals are more Th2 biased. Whether increased ICOS expression affects Th2 differentiation or is a marker of Th2 differentiation remains to be elucidated. Alternatively, increased ICOS expression may lead to decreased responses to Th1-type stimuli and tip the balance toward Th2 responses.

Whether the –1413/–693 variation per se alters the expression of ICOS and subsequently affects B cell Ig production remains to be directly proven. However, the type 1 diabetes susceptibility locus, Idd5.1 in NOD mice, contains ICOS (28, 29). Interestingly, ICOS expression is higher on activated NOD T cells than B6/B10 T cells, and this difference in expression was mapped to a 2.1-Mb region encompassing ICOS and CTLA4. This region also accounted for differences among strains in disease severity in murine experimental autoimmune encephalomyelitis, suggesting that the level of ICOS expression may directly influence T cell effector function. Additionally, variation in ICOS surface expression levels in a murine model has been shown to correlate with distinct populations of cytokine-producing cells (30). High ICOS-expressing T cells were IL-10 producing, whereas medium ICOS-expressing T cells were IL-4 and IL-13 producing. These data support the idea that the level of ICOS expression influences differentiation and cytokine production. Together, our study and these reports argue that genetic variation in the 5' promoter region of ICOS may directly affect T cell effector function in humans and thereby bias immune responses.

	Acknowledgments

 
We thank C. Bourgain for assistance with statistical analysis in the Hutterites, A. Welcher (Amgen Inc., Thousand Oaks, CA) for providing reagents for this study, G. Franzoso for anti-p65 Ab and technical advice, and A. M. Dumitrescu, S. Yoshinaga, A. Tesciuba, K. Blaine, J. Solway, and M. Alegre for helpful discussions and assistance during these studies.

	Disclosures

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The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants 5T32-DC00058, HL56399, HL66533, 5T32-AI07077-04, AI56352, and AI50180.

² J.M.P. and R.A.S. contributed equally and should be considered co-first authors.

³ Address correspondence and reprint requests to Dr. Anne I. Sperling, The University of Chicago, MC6026, Room M624, 5841 South Maryland Avenue, Chicago, IL 60637. E-mail address: asperlin{at}uchicago.edu

⁴ Abbreviations used in this paper: SPT, skin prick test; SNP, single nucleotide polymorphism; LD, linkage disequilibrium.

Received for publication September 30, 2004. Accepted for publication May 30, 2005.

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