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Identification of T Cell Determinants on Human Type II Collagen Recognized by HLA-DQ8 and HLA-DQ6 Transgenic Mice¹

Christopher J. Krco^*, Shohei Watanabe^*, Jerry Harders^*, Marie M. Griffths, Harvinder Luthra and Chella S. David^*

Departments of ^* Immunology and Rheumatology, Mayo Clinic, Rochester, MN 55905; and Research Service, Veterans Affairs Medical Center and Rheumatology Division, University of Utah, Salt Lake City, UT 84148

	Abstract

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HLA-DQA1*0301 and HLA-DQB1*0302 genes encoding the HLA-DQ8 molecule and HLA-DQA1*0103 and HLA-DQB1*0601 genes encoding the HLA-DQ6 molecule were introduced into H-2A^o knockout mice. Three lines of transgenic mice were established: HLA-DQ8, HLA-DQ6, and HLA-DQ86. HLA-DQ8 mice are susceptible to collagen-induced arthritis, while HLA-DQ6 mice are resistant. HLA-DQ86 mice develop polychrondritis in addition to arthritis. Transgenic mice were primed and challenged with individual synthetic peptides representing human type II collagen. A total of 101 synthetic peptides were tested in each transgenic line of mice. HLA-DQ8 mice responded to 15 synthetic peptides representing all cyanogen bromide fragments. In contrast, HLA-DQ6 mice responded to a subset of the peptides recognized by HLA-DQ8 T cells. HLA-DQ86 mice, although exhibiting diminished responses to the majority of HLA-DQ8-restricted determinants, elicited enhanced responses to two peptides. In addition, HLA-DQ86 mice respond to two unique peptide determinants contained within cyanogen bromide fragments CB10 and CB11 showing the significance of mixed isotype dimers in the immune response. The determinants recognized by the HLA-DQ transgenic mice are distinct from those previously identified using conventional laboratory mice. These results suggest that human class II transgenic mice offer a means of identifying human class II-restricted epitopes associated with potential human autoantigens.

	Introduction

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Rheumatoid arthritis (RA)³ is a chronic inflammatory disease of the joints resulting in damage to cartilage. Type II collagen (CII) is a major component of joint articular cartilage (1, 2). Both anti-CII Abs and T cell reactivity to CII have been detected in synovial tissues and fluids of RA patients (3, 4, 5, 6, 7). These observations have led to the concept that autoreactivity to CII may play a significant role in RA pathogenesis (8). Arthritic syndromes reminiscent of human RA can be induced in rodents following administration of heterologous CII (8, 9, 10, 11, 12). The role of MHC, TCR, and genetic background genes in experimental collagen-induced arthritis (CIA) has been reviewed (13).

Some HLA class II genes, especially the HLA-DR4Dw4 subtype (HLA-DRB1*0401), have been associated with RA predisposition (14, 15, 16). However, it is well appreciated that HLA genes are inherited as a haplotype such that linkage disequilibrium frequently exists between certain HLA-DR and HLA-DQ genes. The presence of some HLA-DQ genes has been associated with certain autoimmune states such as diabetes, Sjogren’s syndrome, myasthenia gravis, and allopoecia areata (17, 18, 19, 20). Depending upon the human population studied, HLA-DQB1*0301 (HLA-DQ7) or HLA-DQB1*0302 (HLA-DQ8) is found in linkage disequilibrium with HLA-DR4 (21). Due in part to this observation and studies in our laboratory with HLA-DQ transgenic mice, we have formulated the concept that certain HLA-DQ genes may also contribute to RA predisposition (22, 23).

To test the hypothesis that the expression of some HLA-DQ molecules can predispose to RA, the HLA-DQA1*0301 and HLA-DQB1*0302 genes encoding the HLA-DQ8 molecule and HLA-DQA1*0103 and HLA-DQB1*0601 genes encoding the HLA-DQ6 molecule were introduced into H-2A^o knockout mice (24). HLA-DQ8 transgenic mice are highly susceptible to CIA following immunization using bovine CII (25). In contrast, HLA-DQ6 transgenic mice are relatively resistant to CIA following heterologous CII challenge. Previously, we have synthesized 101 overlapping peptides representing the mature -chain of human CII and have identified three determinants recognized by the H-2A^q molecule of DBA/1 mice (26). It has been reported that HLA-DQ8 molecules bind a large number of human CII peptides (27). However, the immunogenic structure of human CII as recognized by HLA-DQ molecules is not known. In this study, we report the identification of 15 human CII epitopes that are immunogenic in HLA-DQ8 and HLA-DQ6 mice.

	Materials and Methods

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Mice

The production of transgenic mice expressing HLA-DQ8 (HLA-DQA1*0301; HLA-DQB1*0302) and HLA-DQ6 (HLA-DQA1*0103; HLA-DQB1*0601) genes in the absence of endogenous mouse class II genes has been previously described (24). Transgenic mice expressing HLA-DQB1*0302 and HLA-DQA1*0103 genes were mated to generate HLA-DQ86-expressing transgenics.

Antigens

The production and sequences of 101 synthetic, overlapping peptides representing the mature -chain of human CII have been published (26). Each peptide is 20 aa in length and contains a 10-residue overlapping sequence with the previous peptide in the panel.

Immunization and in vitro cultures

A total of 200 µg of peptide emulsified in CFA (Difco, Detroit, MI) was administered as s.c. injections into the tails and hind footpads of mice (26). Each mouse received 200 µg of peptide. One mouse was immunized per peptide. Each peptide was tested three to five times in independent assays on different days using freshly prepared emulsions. Seven days post injection, the draining lymph node cells were challenged in vitro. The extent of T cell activation after 48 h of in vitro culture was determined by measuring the incorporation of [³H]thymidine. Results are expressed as cpm ( cpm) and are calculated as cpm = (mean cpm of triplicate cultures containing Ag) - (mean cpm of triplicate cultures containing media alone). Mean cpm of cultures containing Con A (Sigma, St. Louis, MO) (positive control) were greater than 200,000. Mean cpm of cultures containing medium alone varied between 1,000 and 4,000. Mean cpm of less than 10,000 were operationally defined as being not significant.

	Results

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T cell responses in HLA-DQ8, HLA-DQ6, and HLA-DQ86 mice to synthetic peptides of human CII

Mice were immunized with individual human CII peptides, and the draining lymph node cells were challenged in vitro. Results are presented as peptide groups corresponding to their relative sequence positions in the classical cyanogen bromide (CB) polypeptides of human CII, as depicted in Table I. Data comparing the HLA-DQ8, HLA-DQ6, and HLA-DQ86 transgenic responses are summarized in Table II.

Peptides F (residues 44–63), G (residues 54–73), and K (residues 94–113) were strongly immunogenic in both HLA-DQ8 and HLA-DQ6 mice (Fig. 1, Table II). However, the mean cpm in responses to peptides F (20,371 vs 63,368), G (40,267 vs 71,629), and K (65,345 vs 25,885) were different when comparing the two transgenic lines, HLA-DQ8 and HLA-DQ6, respectively. All other peptides representing CB6,12 residues of human CII were not immunogenic in either HLA-DQ8 or HLA-DQ6 mice (mean cpm <5,000). Moreover, HLA-DQ86 transgenic mice were unresponsive to synthetic peptides representing residues 1–122 (CB6,12) of human CII.

View larger version (14K): [in this window] [in a new window]   FIGURE 1. Responses of HLA-DQ transgenic mice to peptides representing human CB6,12 polypeptide. Mice were immunized and challenged in vitro with individual peptides. Draining lymph node cells were cocultured with medium alone, Con A, or immunizing peptide. Cell proliferation was assessed by determining the extent of [3H]thymidine incorporation. Data are expressed as cpm after 48 h of in vitro culture. One mouse was immunized per peptide. Each peptide was tested three to five times in independent assays on different days using freshly prepared emulsions.

HLA-DQ8, HLA-DQ6, and HLA-DQ86 mice (Fig. 2, Table II) responded modestly (mean cpms of 25,362, 23,981, and 22,222, respectively) to in vitro challenge involving peptide 7 (residues 184–203). However, HLA-DQ8 mice also responded to peptides 6 (residues 174–193; mean cpm of 18,995), 8 (residues 194–213; mean cpm of 23,011), and 17 (residues 284–303; mean cpm of 31,445). HLA-DQ6 mice were hyporesponsive (mean cpm <9,200) to these three peptides. All other peptides comprising the CB11 polypeptide were not stimulatory in either HLA-DQ8 or HLA-DQ6 mice (mean cpm < 11,400). DQ86 mice responded to peptides 6 and 8 (mean cpm of 15,213 and 21,052, respectively), but not to peptide 17 (mean cpm of 8,622). Only HLA-DQ86 mice responded (mean cpm of 35,667) to peptide 23 (residues 344–363).

View larger version (14K): [in this window] [in a new window]   FIGURE 2. Responses of HLA-DQ transgenic mice to peptides representing human CB11 polypeptide. Mice were immunized and challenged in vitro with individual peptides. Draining lymph node cells were cocultured with medium alone, Con A, or immunizing peptide. Cell proliferation was assessed by determining the extent of [3H]thymidine incorporation. Data are expressed as cpm after 48 h of in vitro culture. One mouse was immunized per peptide. Each peptide was tested three to five times in independent assays on different days using freshly prepared emulsions.

Only peptide 43 (residues 544–563) was stimulatory in both HLA-DQ8 (mean cpm 50,176) and HLA-DQ6 (mean cpm 42,202) mice (Fig. 3). Although HLA-DQ6 mice did respond marginally to peptide 39 (residues 504–523; mean cpm 19,010), they did not respond to any other CB8 synthetic peptide (mean cpm < 8,300). In contrast, HLA-DQ8 mice responded to several additional CB8 peptides, including peptide 32 (residues 434–453; mean cpm of 30,870), 33 (residues 444–463; mean cpm of 23,011), 35 (residues 464–483; mean cpm of 20,355), and 38 (residues 494–513; mean cpm of 21,066). HLA-DQ86 mice responded to peptide 33 (mean cpm of 34,641).

View larger version (18K): [in this window] [in a new window]   FIGURE 3. Responses of HLA-DQ transgenic mice to peptides representing human CB8 polypeptide. Mice were immunized and challenged in vitro with individual peptides. Draining lymph node cells were cocultured with medium alone, Con A, or immunizing peptide. Cell proliferation was assessed by determining the extent of [3H]thymidine incorporation. Data are expressed as cpm after 48 h of in vitro culture. One mouse was immunized per peptide. Each peptide was tested three to five times in independent assays on different days using freshly prepared emulsions.

As shown in Fig. 4 and Table II, the HLA-transgenic mice showed strong proliferative responses to certain of the CB10 peptides. HLA-DQ8 mice responded very strongly to peptides 44 (residues 554–573, mean cpm of 90,169), strongly to peptides 43 (mean cpm of 50,176) and 64 (residues 724–773; mean cpm of 53,222), and moderately to peptide 61 (residues 724–743; mean cpm of 26,704). HLA-DQ6 mice (Fig. 4) were also strongly responsive to peptide 43 (mean cpm of 42,202), but were hyporesponsive to peptides 61 and 64 (mean cpm <3,000) and developed a substantially weaker response to peptide 44 (mean cpm of 24,752) than did HLA-DQ8 mice. Although HLA-DQ86 mice did not respond to peptides 43, 61, or 64 (mean cpm < 7,200), enhanced responses were measured against peptide 44 (mean cpm of 121,434). Moreoever, HLA-DQ86 mice uniquely responded (mean cpm of 35,295) to peptide 73 (residues 844–863).

View larger version (16K): [in this window] [in a new window]   FIGURE 4. Responses of HLA-DQ transgenic mice to peptides representing human CB10 polypeptide. Mice were immunized and challenged in vitro with individual peptides. Draining lymph node cells were cocultured with medium alone, Con A, or immunizing peptide. Cell proliferation was assessed by determining the extent of [3H]thymidine incorporation. Data are expressed as cpm after 48 h of in vitro culture. One mouse was immunized per peptide. Each peptide was tested three to five times in independent assays on different days using freshly prepared emulsions.

Only one peptide (78; residues 894–913) elicited a response (Fig. 5, Table II) in either HLA-DQ8 (mean cpm of 29,820) or HLA-DQ6 (mean cpm of 17,774) mice. All other peptides representing CB9,7 residues of human CII were not immunogenic (mean cpms <10,000). HLA-DQ86 mice did not respond to any of the synthetic peptides representing CB9,7.

View larger version (12K): [in this window] [in a new window]   FIGURE 5. Responses of HLA-DQ transgenic mice to peptides representing human CB9,7 polypeptide. Mice were immunized and challenged in vitro with individual peptides. Draining lymph node cells were cocultured with medium alone, Con A, or immunizing peptide. Cell proliferation was assessed by determining the extent of [3H]thymidine incorporation. Data are expressed as cpm after 48 h of in vitro culture. One mouse was immunized per peptide. Each peptide was tested three to five times in independent assays on different days using freshly prepared emulsions.

	Discussion

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CIA-susceptible HLA-DQ8 transgenic mice responded to one or more peptides representing each of the five major CB polypeptides of human CII: CB6,12 (peptides F, G, K); CB11 (peptides 7, 8, 17); CB8 (peptides 32, 33, 35, 38, 43); CB10 (peptides 43, 61, 64), and CB9,7 (peptide 78). Interestingly, 7 of the 15 peptides span regions of the human CII reported capable of binding to HLA-DQ8 molecules in vitro (Table II). In contrast, CIA-resistant HLA-DQ6 mice are capable of responding vigorously only to a relatively small subset of peptides (F, G, and 43) that are immunogenic in HLA-DQ8 mice. HLA-DQ6 mice exhibit diminished or hyporesponsiveness to the remaining 12 HLA-DQ8 immunogenic peptides. Furthermore, we have not found a human CII peptide that elicits a strong response in HLA-DQ6 mice and to which HLA-DQ8 mice are unresponsive. Thus, CIA susceptibility in HLA-DQ8 mice correlates with a broad T cell reactivity to multiple epitopes scattered along the entire CII molecule. As might be expected, CIA resistance in HLA-DQ6 mice associates with a correspondingly lower and relatively restricted CII peptide responsiveness.

Transgenic mice expressing HLA-DR4 (DRB1*0401), a gene implicated in human RA, recognize very few epitopes on human CII. Mice expressing HLA-DRB1*0401 transgene respond to a determinant within residues 260–273 (28, 29, 30). Peptide-binding analyses have confirmed the ability of peptides encompassing residues 260–273 to strongly bind to HLA-DR4 molecules (28). In addition, weaker binding determinants have been localized within residues 21–33, 84–96, 231–243, 258–270, and 462–474. With the exception of residues 462–474, which partially corresponds to our peptide 35 (residues 464–483) and elicits an intermediate response in HLA-DQ8 but not HLA-DQ6 mice, these regions were not immunogenic.

Suprisingly, HLA-DQ86 mice, which develop CIA complicated by polychondritis, were also hyporesponsive to the majority of HLA-DQ8- or HLA-DQ6-restricted immunogenic peptides. However, in one instance (peptide 44), HLA-DQ86 mice exhibited a greatly enhanced response. Interestingly, in two instances (peptides 23 and 73), HLA-DQ86 mice responded strongly to peptides that were completely nonimmunogenic in HLA-DQ8 or HLA-DQ6 mice, thus demonstrating that an exceptionally strong immune response to a limited part of the human CII molecule can still drive arthritis and pathogenic anti-CII immune responses. The data further suggest that the polychondritis of HLA-DQ86 mice (which is not exhibited by HLA-DQ8 nor HLA-DQ6 mice) may reflect the strikingly different peptide response pattern of HLA-DQ86 mice to particular regions of the CB10 peptides (Table II). In other studies (M.M.G., unpublished data), HLA-DQ86 mice were found to develop very high IgG Ab responses to renatured CB10 fragments.

CII from diverse species (human, mouse, bovine, pig, and chick) have been utilized to induce CIA in a variety of rodent models. Published sequence data have revealed sequence conservation among heterologous CII molecules. When the HLA-DQ8 immunostimulatory peptide sequences are compared with published CII sequence data, some interesting deductions can be made. Overall, those peptides that are immunogenic in HLA-DQ8 or HLA-DQ6 mice are between 90–100% homologous to mouse or bovine CII. It is interesting to note that the two most immunogenic peptides (K and 44) are 100% homologous between human CII and mouse CII and can be viewed as autoantigenic epitopes for both humans and mice. In a similar fashion, the HLA-DQ86-restricted peptides 23 and 73 are also autoantigens for the two species. This comparison emphasizes and validates the utility of HLA-transgenic mice, and the HLA-DQ8 and HLA-DQ6 mice in particular, as tools for in vivo investigations of HLA class II regulation of pathological autoimmune responses to the CII autoantigen in rheumatic diseases.

The relationship between immunogenicity and arthritogenicity of the immunostimulatory peptides is currently under investigation in our laboratory. One possibility is that the severity of the arthritis in HLA-DQ8 mice is the cumulative immune responses to multiple collagen epitopes. This finding suggests two possible events that may contribute to the severe disease in these mice. One, HLA-DQ8 may be a promiscuous molecule capable of presenting multiple epitopes not only in the periphery, but also in the thymus. Two, positive selection of several HLA-DQ8-restricted T cells in the thymus may generate HLA-DQ8-restricted T cells capable of recognizing certain peptides in the periphery. HLA-DQ6 mice develop less severe arthritis because of a less vigorous response to a smaller set of collagen epitopes.

This is the first demonstration that the HLA-DQ8 and HLA-DQ6 chains can pair, form a stable molecule expressed on the cell surface, and present unique peptides to T cells. The enhanced response to a unique set of peptides recognized by HLA-DQ86 mice may result in serological cross-reaction with collagen in the ear initiating polychondritis (31). The enhanced Ab binding to CB10 measured in HLA-DQ86 mice may be a major contributing factor in the different clinical syndrome presented in these mice. In humans, such interisotypic chain pairing could generate immune responses to Ags in heterozygous individuals not present in parental haplotypes. As we have shown in our studies in auncular polychondritis (31), such responses could also cause disease in humans.

We have determined the antigenic regions of human CII as defined using direct peptide immunizations. Seven of the fifteen peptides span regions of the human CII molecule that bind to HLA-DQ8 molecules. Peptides F and G (spanning residues 44–73) correspond to collagen peptide region 56–80 that has been reported capable of binding to HLA-DQ8. Other peptides, including 17 (residues 284–303), 33 (444–463), 38 (residues 494–513), 43 (residues 544–563), and 44 (residues 554–573), encompass human CII sequences eluted from HLA-DQ8 molecules. Our data demonstrate that direct peptide immunization is one means of identifying immunostimulatory peptides from a pool of HLA-class II-eluted polypeptides. HLA-DQ8 peptide elution data is far from being exhaustive, and it remains a distinct possibility that additional human CII-binding sequences will be identified. We have attempted direct immunization using intact human collagen, followed by in vitro challenge using CII or peptides. We have not consistently been able to detect reliable and reproducible T cell responses. One approach to addressing this dilemma would involve direct immunization using purified human CB polypeptides, followed by in vitro challenge using the appropriate set of overlapping synthetic peptides. Such an approach might be helpful in delineating naturally processed peptides from cryptic regions that are not normally presented by HLA-DQ molecules. Upon having identified immunogenic peptides, minimal epitope mapping utilizing truncated peptides could be undertaken to identify core determinants as well as candidate HLA-DQ8-, HLA-DQ6-, and HLA-DQ86-associated sequence motifs.

In summary, we have determined that CIA-susceptible HLA-DQ8 mice respond to a unique set of human CII peptides that differs completely from the classically used DBA/1 mice. These results suggest that in the human population, heretofore unappreciated regions of the human CII molecule may play a role in RA. Experimentation using HLA class II transgenics may result in new experimental paradigms for RA immunotherapies.

	Acknowledgments

 
We thank Julie Hanson and her staff for outstanding mouse husbandry. We thank Dr. Dan McCormick and his staff (Jane Liebenow and Denise Walker) for superb technical support in synthesizing and purifying the peptides used in these investigations. We thank Mary Brandt for her secretarial assistance.

	Footnotes

 
¹ This work was supported by National Institutes of Health Grants AI 14764 and AR 30752, and Minnesota Arthritis Foundation. M.M.G. is supported by the Veterans Affairs BioMedical Research Merit Funding.

² Address correspondence and reprint requests to Dr. Chella S. David, Department of Immunology, Mayo Foundation, 200 First Street NW, Rochester, MN 55905. E-mail address:

³ Abbreviations used in this paper: RA, rheumatoid arthritis; CB, cyanogen bromide; CIA, collagen-induced arthritis; CII, type II collagen

Received for publication March 5, 1999. Accepted for publication May 12, 1999.

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