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The Journal of Immunology, 2001, 167: 5543-5547.
Copyright © 2001 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Leukocyte Receptor Complex-Encoded Immunomodulatory Receptors Show Differing Specificity for Alternative HLA-B27 Structures1

Rachel L. Allen2,*, Tim Raine*, Anja Haude*, John Trowsdale* and Michael J. Wilson*,{dagger}

* Department of Pathology, University of Cambridge, Cambridge, United Kingdom; and {dagger} Discovery Research, GlaxoSmithKline, Stevenage, United Kingdom


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We studied recognition of the disease-associated HLA-B27 allele by immunomodulatory receptors encoded within the leukocyte receptor complex. HLA class I are ligands for members of the killer Ig receptor (KIR) and Ig-like transcript (ILT)/LIR/LILR families (the new LILR nomenclature is described at www. gene.ucl.ac.uk/nomenclature/genefamily/lilr.html). Members of these families bound HLA-B27 in both classical and {beta}2 microglobulin-independent forms. Classical complexes bound ILT2, ILT4, and LIR6 transfectants but not ILT1, ILT3, or ILT5. A free H chain form of HLA-B27 bound ILT4 and LIR6. Both forms of HLA-B27 bound KIR3DL1 transfectants. HLA-B27 free H chain bound CD14+ cells in PBL from healthy controls, consistent with ILT4 expression on monocytes. Alternative recognition of different forms of HLA-B27 by KIR or ILT could influence their immunomodulatory function and may imply a role in inflammatory disease.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Spondyloarthropathies show a striking association with the HLA-B27 allele. Because class I proteins present peptides for TCR recognition, the disease association of HLA-B27 is widely assumed to imply a role for the TCR. Still, the underlying pathological mechanisms of spondyloarthropathy remain unknown. Class I also act as ligands for immunomodulatory receptors, particularly those encoded within the leukocyte receptor complex on chromosome 19. This includes two families of class I-specific regulatory receptors—the killer cell Ig receptors (KIR)3 and the Ig-like transcripts (ILT). Given their class I specificity and immunomodulatory effects, KIR and ILTs might play an active role in class I-associated disease.

Members of the KIR family recognize subsets of HLA-A, -B, or -C alleles and are highly polymorphic (1). HLA-B27 is a member of the Bw4 subgroup of alleles, defined by residues at positions 77–83 and recognized by KIR3DL1 (2, 3). Three levels of variation determine the repertoire of KIR expression for any given T or NK cell clone: 1) genomic variations in the presence/absence of different KIR loci, 2) allelic variations within KIR loci, and 3) stochastic expression of individual KIR in a given clone. Referred to as NK receptors, KIR are also expressed on subsets of CD4, CD8, and {gamma}{delta} T cells (4).

Adjacent to the KIR are ILT loci (also known as LIR, LILR, and CD85). Two members of this family, ILT2 (LIR1/LILRB1) and ILT4 (LIR2/LILRB2), have been shown to recognize a broad range of HLA class I (5, 6, 7). ILTs are predominantly expressed on cells of the myelomonocytic lineage, and T and B cell subsets (8, 9).

KIR and ILTs modulate activation of other immune receptors. Inhibitory ILTs can suppress Fc receptor or TCR signaling on monocytes and T cells respectively (8, 10), while KIR can down-modulate TCR-mediated T cell activation (4). Immunoreceptor tyrosine-based inhibition motifs in the cytoplasmic domain of these inhibitory receptors mediate their inhibitory functions. ILT2 is an inhibitory receptor with a wide expression pattern (9). Little is known about the physiological role of ILT4, which is predominantly expressed on myelomonocytic cells. Activating receptors have a short cytoplasmic tail and exert their function via associated adapter proteins bearing immunoreceptor tyrosine-based activation motifs. Activating KIR have been shown to act as costimulators on T cells (11).

HLA class I exist at the cell surface as a heterodimer of H chain and {beta}2 microglobulin ({beta}2m), which present peptide for TCR recognition. They also exist in structures referred to as empty class I and free H chains (FHC). FHC usually arise by cell surface dissociation of heterodimers (12) and are often regarded as immunologically inert. However, unusual properties of HLA-B27 include an ability of FHC to maintain the peptide binding groove in vitro (13). FHC of HLA-B27 may confer arthritis on transgenic mice. Disease incidence was reduced in this model using FHC-specific Abs (14). Thus, the potential recognition and role of FHC in disease has become a topic of interest (15, 16, 17).

If unfolded HLA-B27 remain at the cell surface in vivo, they might act as a ligand for certain immune receptors. HLA-B27 can reach the cell surface in a {beta}2m-deficient cell line to associate with exogenous {beta}2m (R. L. Allen, unpublished results). Although HLA-B27 FHC or reassociated complexes may not acquire appropriate peptides for presentation to TCR, they may still be able to engage more generic receptors such as KIR or ILTs. To test this hypothesis, we generated fluorogenic complexes of normal and FHC forms of HLA-B27 and tested them for their ability to bind KIR and ILT receptors.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Constructs

HLA-B27 constructs were as previously described (13). Vectors encoding FLAG-ILT1, FLAG-ILT2, ILT3, FLAG-ILT4, FLAG-ILT5, FLAG-ILT7, FLAG-LIR6, and cDNA encoding the NKAT3 allele of KIR3DL1 were a kind gift from M. Colonna (Basel Institute, Basel, Switzerland). 3DL1-GFP was generated by PCR of NKAT3 cDNA to allow cloning into pEGFP-N2 (Clontech Laboratories, Palo Alto, CA).

Abs and tetramers

HLA-B27 protein complexes were generated and refolded around the HIV gag epitope (as described in Ref. 13). Abs were DX9 (kind gift from J. Phillips, DNAX, Palo Alto, CA), anti-FLAG Ab M2 (Sigma-Aldrich, Poole, U.K.), anti-ILT1 and ILT3 (M. Colonna, Basel Institute), and anti-LIR6 (M. Torkar, R. Barten, and M. J. Wilson, manuscript in preparation).

Cells and stainings

Cells were transiently transfected using LipofectAMINE 2000 (Life Technologies, Paisley, U.K.). All constructs were transfected into the 293T cell line. PBL were separated by centrifugation over Lymphoprep (Nycomed, Oslo, Norway) and washed in RPMI 1640 (Life Technologies) before staining. Cells were stained for flow cytometry according to standard protocols.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Different forms of HLA-B27 bind overlapping sets of ILT receptors

The aim of this study was to explore recognition of different forms of HLA-B27 by immunomodulatory receptors. Classical heterodimers and FHC of HLA-B27 form stable structures in vitro (13). These complexes (termed HLA-B27/{beta}2m and HLA-B27 H chain structure (HC-B27), respectively) can be fluorescence-tagged to generate reagents for flow cytometry. Similar complexes have been used to characterize interactions of HLA with ILT receptors (5).

Individual receptors were tested for their ability to bind HC-B27 and HLA-B27/{beta}2m. Constructs encoding ILT1, ILT2, ILT3, ILT4, ILT5, ILT7, and LIR6 were transiently expressed in 293T cells and studied for binding. As before (5), HLA-B27/{beta}2m complexes bound both ILT2 and ILT4. HLA-B27 also bound the previously uncharacterized activating receptor LIR6(LILRA1). In contrast, HC-B27 complexes bound ILT4 and LIR6 but not ILT2 (see Fig. 1Go). ILT2, ILT4, and LIR6 binding of HLA-B27/{beta}2m and HC-B27 could be blocked with class I-specific Abs (HC10 and W6/32; data not shown). ILT-specific Abs generated within our laboratory failed to block these interactions (data not shown). However, our Abs showed broad cross-reactivity for multiple ILTs and are unlikely to engage the binding site of individual receptors. These experiments show differential detection of two forms of HLA-B27 by different ILT receptors.



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  		FIGURE 1. HLA-B27 complexes bind ILT/LIR receptors. Fluorogenic HLA-B27/{beta}2m, HC-B27 complexes, and an extravidin-PE control were used to stain 293T cells transiently transfected with various receptors and an untransfected control. Receptor expression was verified by anti-FLAG staining.

 
HLA-B27 FHC bind to a KIR receptor

Having shown that an FHC form of HLA-B27 can engage ILT receptors we then studied its ability to bind an appropriate KIR. KIR are specific for subsets of alleles defined by residues within the peptide binding groove. As a Bw4 subgroup member, HLA-B27 is a ligand for KIR3DL1. Both HLA-B27/{beta}2m and HC-B27 bound KIR3DL1 transfectants. Neither HLA-B27/{beta}2m nor HC-B27 stained transfectants expressing the HLA-C-specific KIR2DL1 (data not shown). A KIR3DL1-GFP construct was used to allow direct comparison of HLA staining with KIR3DL1 expression. HC-B27 stained 3DL1-GFP-positive cells over a range of expression levels (see Fig. 2Gob) and was blocked by preincubation with the 3DL1-specific Ab DX9 (see Fig. 2Goc). Similarly, HLA-B27/{beta}2m stained transfectants with high 3DL1-GFP expression levels (see Fig. 2God) in a specific interaction that could be blocked with DX9 (see Fig. 2Goe).



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  		FIGURE 2. HLA-B27 complexes bind a KIR receptor. 293T cells transfected with KIR3DL1-GFP were stained with an extravidin-PE control (a), HC-B27 (b), HC-B27 with DX9 preblock (c), HLA-B27/{beta}2m (d), and HLA-B27/{beta}2m with DX9 preblock (e).

 
HLA-B27 FHC bind PBL

Having defined potential receptors for HLA-B27 FHC using transfectants, we sought to determine their potential recognition by PBL. To rule out the possibility of TCR recognition, HC-B27 was refolded around the HLA-B27 restricted HIV gag epitope. Samples were from HIV-negative healthy volunteers. Two-color analysis allowed various cell populations to be analyzed. Representative analyses are shown in Fig. 3Go. No significant staining was seen for CD56+ or CD3+ cell populations, subsets of which are known to express KIR. A small percentage of CD19+ B cells were consistently stained with HC-B27 in all controls. Extensive HC-B27 staining was observed only for CD14+ myelomonocytic cells. These patterns are characteristic of ILT expression (6). Furthermore, HC-B27 staining was brightest on the CD14mid population compared with CD14bright monocytes (Fig. 3God), consistent with previous studies of ILT4 (7).



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  		FIGURE 3. HLA-B27 FHC bind peripheral blood myelomonocytic cells. PBL from healthy volunteers were stained with HC-B27 or an extravidin-PE control and anti-CD3 (a), anti-CD19 (b), anti-CD56 (c), and anti-CD14 (d and e). An electronic gate was set on lymphoid cells (a–c) or myelomonocytic cells (d and e).

 
Given its ability to bind KIR3DL1 transfectants, it was surprising that no HC-B27 staining was seen on cell populations known to express this receptor. It is possible that, due to the polymorphic nature of KIR, none of the controls expressed an appropriate receptor. KIR3DL1 is also allelic with an as yet uncharacterized activating receptor, KIR3DS1. Controls were chosen following genotype analysis to include one KIR3DL1 homozygote, one KIR3DS1 homozygote, and a heterozygote. An HLA-B27-positive control was also included. All volunteers showed similar HC-B27 binding patterns in terms of the cell types and relative numbers stained. It is unlikely that the KIR3DL1 alleles in these samples are all nonbinding variants, but this cannot be ruled out. KIR3DL1 expression was confirmed by staining with DX9 (data not shown). The lack of HC-B27 staining on NK and T cells may reflect KIR3DL1 expression levels or receptor density. KIR expression on T cells is usually restricted to memory CTL (18) and CD4+CD28- T cells (19).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We show that a disease-associated HLA allele can engage immunomodulatory receptors in both {beta}2m-associated and FHC forms. Recognition of FHC by class I-specific receptors is not unprecedented; another KIR has been shown to recognize empty class I (20), and paired inhibitory receptors, probable murine orthologs of the ILTs, can achieve a reasonable degree of activation in {beta}2m-deficient mice (21).

Of the receptors tested, only ILT2 could clearly distinguish HC-B27 and HLA-B27/{beta}2m. One interesting observation was that receptors may differ in their affinity for the two structures. Unlike Ab stainings, the low-affinity interaction between these proteins and their receptors allows rough comparisons of affinity to be made. Detailed binding studies would determine the kinetics of KIR and ILT interactions with different class I. However, as can be seen in Fig. 2Go (and in many repeated experiments), ILT4 may have a higher affinity for HC-B27, while LIR6 has comparable affinities for FHC and heterodimer forms. This can be visualized in terms of the number of receptor-positive cells which bind fluorogenic ligand (see Fig. 4Go). It is worth noting that the FHC form used in our study was a homodimer (13), so the ratio of H chains between classical complexes and HC-B27 was thus 2:1. FHC exist as dimers or in clusters at the cell surface in vivo (13, 22, 23), which could have profound effects on receptor engagement. If ILT and KIR play a role in inflammatory disease, their varying affinities for different alleles and forms of HLA could be highly relevant.



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  		FIGURE 4. {beta}2m-associated and FHC forms bind ILT receptors to varying degrees. Values shown represent the percentage of receptor positive cells (as quantitated by Ab binding) stained by nonsaturating levels of HC-B27 or HLA-B27/{beta}2m

 
ILT2 binds the conserved {alpha}3 domain of class I (24) but did not recognize HC-B27. The broad specificity of ILT4 would indicate that it also binds a conserved region such as the {alpha}3. However, ILT4 bound both normal and HC-B27 forms, indicating an alternative binding site and a broader range of specificity than previously known. Our ongoing work indicates that LIR6 has a more restricted specificity than ILT2 or ILT4 (R. Allen, unpublished results). The majority of HC-B27 staining in healthy controls is likely to reflect ILT4 expression. ILT4 is predominantly expressed on CD14+ monocytes and dendritic cells; although its cDNA can be detected in B cells (6), Ab staining has yet to detect its presence there. Thus, the low-level HC-B27 staining of B cells might reflect LIR6 expression or another, undetermined receptor. This is the first study to identify a ligand for LIR6. LIR6 protein has yet to be identified in any cell type but is likely to be found in monocytes or B cells (6).

The {alpha}1 helix of HLA-B is critical for KIR3DL1 binding, particularly residue 80 (2, 25). KIR recognition of an FHC form may be unique to HLA-B27, which can maintain some conformation without {beta}2m (13). Despite a lack of evidence for KIR engagement of FHC in healthy controls, expression levels and numbers of KIR+ cells are likely to alter in disease. Detailed study of expression patterns and repertoire in spondyloarthropathy might indicate which, if any, play a role in disease.

We believe that ILT and KIR could play a role in HLA-B27-associated disease through recognition of normal and/or unfolded structures. So far, little is known about how ILTs act as immunomodulators in disease. ILT4 is expressed at high levels on macrophages, one of the main cell populations to infiltrate the inflamed joint in spondyloarthropathy. Transfer experiments have directly implicated macrophages in the disease process (26), and it will be important to determine how HLA-B27 recognition by ILT4 and/or LIR6 may influence macrophage function.

There is more evidence for KIR immunomodulation in disease. T cells expressing memory and activation markers are recruited into inflamed joints (27). Large numbers of both CD4 and CD8 KIR+ T cells could then be subject to HLA-B27-mediated immunomodulation in the joint, irrespective of their Ag specificity. Allele association studies could be useful for determining the relevance of KIR in disease. One activating KIR has already been implicated as a risk in rheumatoid arthritis (28). KIR3DL1 is highly polymorphic, and specificities of its individual alleles are likely to vary (29). If KIR and ILTs play a role in spondyloarthropathy, transgenic and allele association studies of afflicted mouse strains (15) may also allow us to identify relevant receptors.

Additional experiments should determine whether FHC are an appropriate ligand for KIR and ILTs in vivo or whether they generate a different outcome from that following classical engagement. However, irrespective of FHC recognition, we can no longer confine ourselves to theories that the class I association of spondyloarthritis directly implicates the TCR. Contrasting disease associations between HLA-B27 subtypes with subtle differences in their peptide binding groove (30) and a degree of peptide specificity (31) are often seen as evidence for TCR involvement. However, NK cells expressing KIR3DL1 show differing responses to HLA-B27+ targets with changes in the peptide binding groove (32) and presented peptides (33, 34). Through interaction with KIR and ILTs, HLA-B27 could influence T cells with a range of TCR specificities, as well as NK cells and monocytes bearing appropriate receptors. This provides one possible mechanism with which to resolve the class I association of spondyloarthritis with a requirement for CD4+ cells. Thus, an important step in the study of class I-associated diseases such as spondyloarthritis may be to address the function of HLA as immunomodulators rather than Ag-presenting molecules.


   Acknowledgments
 
We thank A. Stewart for helpful discussion.


   Footnotes
 
1 This work was supported by the Arthritis Research Council and the Wellcome Trust. Back

2 Address correspondence and reprint requests to Dr. Rachel L. Allen, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, U.K. E-mail address: rla25{at}mole.bio.cam.ac.uk Back

3 Abbreviations used in this paper: KIR, killer Ig receptor; ILT, Ig-like transcript; {beta}2m, {beta}2 microglobulin; FHC, free H chain; HC-B27, HLA-B27 H chain structure. Back

Received for publication August 20, 2001. Accepted for publication September 25, 2001.


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 Results
 Discussion
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V. Montserrat, B. Galocha, M. Marcilla, M. Vazquez, and J. A. Lopez de Castro
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T. Raine, D. Brown, P. Bowness, J. S. Hill Gaston, A. Moffett, J. Trowsdale, and R. L. Allen
Consistent patterns of expression of HLA class I free heavy chains in healthy individuals and raised expression in spondyloarthropathy patients point to physiological and pathological roles
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M. Shiroishi, K. Kuroki, L. Rasubala, K. Tsumoto, I. Kumagai, E. Kurimoto, K. Kato, D. Kohda, and K. Maenaka
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M. J. Turner, D. P. Sowders, M. L. DeLay, R. Mohapatra, S. Bai, J. A. Smith, J. R. Brandewie, J. D. Taurog, and R. A. Colbert
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M. Vales-Gomez, M. Shiroishi, K. Maenaka, and H. T. Reyburn
Genetic Variability of the Major Histocompatibility Complex Class I Homologue Encoded by Human Cytomegalovirus Leads to Differential Binding to the Inhibitory Receptor ILT2
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S. Kollnberger, L. A. Bird, M. Roddis, C. Hacquard-Bouder, H. Kubagawa, H. C. Bodmer, M. Breban, A. J. McMichael, and P. Bowness
HLA-B27 Heavy Chain Homodimers Are Expressed in HLA-B27 Transgenic Rodent Models of Spondyloarthritis and Are Ligands for Paired Ig-Like Receptors
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T. M. Tran, N. Satumtira, M. L. Dorris, E. May, A. Wang, E. Furuta, and J. D. Taurog
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D. Belkin, M. Torkar, C. Chang, R. Barten, M. Tolaini, A. Haude, R. Allen, M. J. Wilson, D. Kioussis, and J. Trowsdale
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L. H. Boyle and J. S. Hill Gaston
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LIR9, an immunoglobulin-superfamily-activating receptor, is expressed as a transmembrane and as a secreted molecule
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E. May, M. L. Dorris, N. Satumtira, I. Iqbal, M. I. Rehman, E. Lightfoot, and J. D. Taurog
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M. Hulsmeyer, R. C. Hillig, A. Volz, M. Ruhl, W. Schroder, W. Saenger, A. Ziegler, and B. Uchanska-Ziegler
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Functional modulation of expanded CD8+ synovial fluid T cells by NK cell receptor expression in HLA-B27-associated reactive arthritis
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