THEME
II. One size fits all: nonclassical MHC molecules fulfill multiple roles in epithelial cell function*

Richard S. Blumberg

Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

    ABSTRACT
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The human major histocompatibility complex (MHC) on chromosome 6 encodes three classical class I genes: human leukocyte antigen-A (HLA-A), HLA-B, and HLA-C. These polymorphic genes encode a 43- to 45-kDa cell surface glycoprotein that, in association with the 12-kDa beta 2-microglobulin molecule, functions in the presentation of nine amino acid peptides to the T cell receptor of CD8-bearing T lymphocytes and killer inhibitory receptors on natural killer cells. In addition to these ubiquitously expressed polymorphic proteins, the human genome also encodes a number of nonclassical MHC class I-like, or class Ib, genes that in general encode nonpolymorphic molecules involved in a variety of specific immunologic functions. Many of these genes, including CD1, the neonatal Fc receptor for immunoglobulin G, HLA-G, the MHC class I chain-related gene A, and Hfe, are prominently displayed on epithelial cells, suggesting an important role in epithelial cell biology.

epithelium; intestine; major histocompatibility complex

    ARTICLE
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IT IS INCREASINGLY recognized that epithelial cells, especially intestinal epithelial cells (IECs), play an important role in innate and adaptive immune functions in addition to their important barrier, absorption, and transport functions (13). A structural motif that is particularly useful to the epithelial cells in fulfilling these immunologic functions is provided by the major histocompatibility complex (MHC) class I-related molecules. Through understanding the composition of these molecules, we can gain insight into their possible functions in epithelial cells.

The basic structure of the MHC class I-related molecules reflects that encoded by the classical MHC class I, or class Ia, genes (14, 32). These genes are encoded within the MHC class I locus on human chromosome 6 and consist of the human leukocyte antigen-A (HLA-A), HLA-B, and HLA-C genes. The open reading frame of these genes consists of structural domains encoded by discrete exons that translate into a ~43- to 45-kDa glycoprotein containing three membrane distal domains (alpha 1, alpha 2, and alpha 3), a transmembrane domain, and a cytoplasmic tail. The most membrane-proximal ectodomain, the alpha 3 domain, provides the major contact sites for the noncovalently associated 12-kDa beta 2-microglobulin (beta 2m) molecule, which is encoded outside the MHC class I locus (38). beta 2m coassociation with the MHC class I heavy chain is prerequisite for functional expression of the protein complex on the cell surface. The most membrane distal alpha 1 and alpha 2 domains contribute to the formation of a series of beta -pleated sheets bounded on the sides by two alpha -helices, forming a groove consisting of a series of pockets capable of binding nine amino acid peptides for presentation to the T-cell receptor (TCR) of CD8-bearing T cells (4, 14). In making contact with the alpha -helices and peptide of the alpha 1 and alpha 2 domains, stabilized by interactions between CD8 on the T cell and clusters of amino acids within the alpha 3 domain of the MHC class Ia molecule (10), the T cell is activated to fulfill its effector function, whether it be proliferation, cytolysis, and/or cytokine secretion. Because the peptides contained within the groove of the MHC class Ia molecules are predominantly derived from the degradation of intracellular molecules by proteasomes, CD8+ T cells are concerned with monitoring the intracellular health of MHC class Ia-bearing cells such as epithelial cells. Delivery of peptides to the MHC class Ia molecule-beta 2m complex is assisted by endoplasmic reticulum-associated proteins, transporters associated with antigen presentation, TAP1 and TAP2 (18). The vast majority of intraepithelial lymphocytes that reside above the basal lamina adjacent to the basolateral surface of the epithelial cells of the intestine are CD8+, indicating the potential importance of this pathway in dealing with deleterious intracellular events as might occur during viral infection, cellular stress, and neoplastic transformation, common events for epithelial cells (5). The MHC class Ia genes display significant allelic polymorphism, due to variations in the amino acid composition of the alpha 1 and alpha 2 domains, each capable of binding a slightly different large array of nonameric peptides (32). In addition, each individual is endowed with six different alleles, predicting that the peptide-binding capacity of an individual is enormous and well suited to dealing with unforeseen antigenic assaults. This pathway of antigen presentation is so efficient that microorganisms, especially viruses, have spent a great deal of evolutionary energy devising strategies to subvert this pathway, such as through the expression of molecules that interfere with cell surface display of MHC class Ia molecules (12, 22) and the generation of decoy molecules encoded by the genome of the pathogen that structurally resemble the MHC class I molecule (11). The common gastrointestinal pathogens herpes simplex virus (12) and cytomegalovirus (11) can accommodate each of these mechanisms of immune evasion, respectively.

The classical MHC class I molecules not only serve as ligands for the TCR of CD8-bearing lymphocytes capable of eliciting cytolysis, but also for killer inhibitory receptors (KIRs) on the cell surface of natural killer (NK) cells (30). When ligated by MHC class Ia, KIRs transmit inhibitory signals to the NK cell bearing the KIR. As a consequence, MHC class Ia-bearing cells are not lysed. However, in the absence of MHC class I, as commonly occurs during neoplasia, including tumors of the epithelium (3), NK-mediated lysis can be induced by ligation of killer-activating receptors (KARs) on the NK cell (30). KIRs exhibit allelic specificity for MHC class Ia molecules, and their binding can be affected by the nonameric peptides presented by specific MHC class Ia alleles. Although NK cells are not a prominent component of the epithelial compartment, the increasing recognition that subsets of T cells, such as so-called natural T cells (29), are capable of expressing KIRs indicates the potential importance of this mechanism of cytolysis induction for T cells and the utility of these regulatory mechanisms at epithelial surfaces.

A plethora of human genes have developed from the ancestral MHC class I gene due to the general utility of this MHC structure in performing discrete tasks of immunologic recognition. These MHC class I-related genes, other than the classical class I genes, are called nonclassical MHC class I molecules or MHC class Ib molecules (10). The MHC class Ib molecules are encoded either by genes linked to the classical HLA-A, HLA-B, and HLA-C genes on chromosome 6 [HLA-E, HLA-F, HLA-G, and HLA-H and MHC class I chain-related gene A (MICA)] or by genes outside the MHC class I locus. These latter genes include the CD1 family and a gene of unknown function, MR1 (21), on chromosome 1, the human homologue of the rodent neonatal Fc receptor for immunoglobulin G (IgG) (FcRn) on chromosome 19, and the zinc-alpha 2-glycoprotein (ZAG), a soluble serum protein of unknown function (36) encoded on chromosome 7 (Table 1). In mouse species, an even larger number of MHC-linked genes are encoded within three genetic loci (Q, T, and M) on chromosome 17 (10).

                              
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Table 1.   MHC class Ib molecules on epithelial cells

These genes are considered MHC class I like on the basis of similarities of exon-intron structure with MHC class Ia molecules (alpha 1-alpha 3 ectodomains, transmembrane domain, and cytoplasmic tail encoded by discrete exons) and dependence on beta 2m for cell surface display and function, with some exceptions. CD1d (see below), MICA (1, 19), and ZAG (36) can be expressed without beta 2m, suggesting an element of independence from beta 2m in function. However, the MHC class Ib molecules differ in their general lack of polymorphism in the amino acid composition of their respective alpha 1 and alpha 2 domains, so that they are considered to be nonpolymorphic (10, 32). This lack of polymorphism, with some exceptions (as described below), suggests that the alpha 1 and alpha 2 domains of the MHC class Ib molecules bind very distinct structures. This further suggests that they have evolved to specialize in binding evolutionarily conserved ligands. In conjunction with other structural information encoded in their primary amino acid sequences, their specific ligand recognition also correlates with specific types of functions as a consequence of ligand binding. Finally, the MHC class I molecules, in contrast to the ubiquitously expressed MHC class Ia molecules, exhibit a restriction in their expression to specific cell types and, naturally, tissues (10). This is especially relevant to human epithelial cells, which appear to be a particularly prominent cell type that exhibits expression of several MHC class Ib molecules, including CD1, FcRn, HLA-G, MICA, and HLA-H.

The human CD1 gene family consists of five genes, CD1A-E (8). A gene product for CD1E has not yet been defined. (By convention, CD1 genes are represented by capital letters and CD1 proteins by lowercase letters.) Nucleotide and deduced amino acid homologies predict that these gene products segregate into two groups: CD1a-c and CD1d. CD1A-C homologues are not present in mice and rats, which contain CD1D homologues highly related to human CD1D. Whereas CD1a-c are expressed by thymocytes and certain professional antigen-presenting cells such as B lymphocytes, Langerhans' cells of the skin, and activated monocytes, CD1d is expressed by thymocytes, B cells, hepatocytes, and, importantly, epithelial cells in a wide variety of organs. CD1b and CD1c appear to function in the presentation of exogenous and, possibly, endogenous lipid antigens to T cells (24). In general, these CD1-restricted lipid-responsive T cells are either CD8+ or lack CD4 and CD8 (double negative). The response of double-negative cells suggests either no need for coreceptor function in TCR binding or the use of another novel, not yet described, coreceptor molecule. The antigen-presenting pathway by which CD1b and CD1c acquire lipid-related antigens is TAP independent and overlaps with that utilized by MHC class II molecules (37). The MHC class II homologies include similarities in the nucleotide sequence within the alpha 3 domain and the presence of a YXXZ motif (tyrosine-amino acid-amino acid-hydrophobic amino acid) in the cytoplasmic tail that controls protein movement to an endocytic compartment in which MHC class II processing occurs. CD1d shares the YXXZ motif with CD1b and CD1c and exhibits a narrow but deep hydrophobic pocket (40), suggesting a similar but unproven capability of binding and presenting exogenous and/or endogenous lipid antigens to T cells generated by a processing pathway that bisects MHC class II. However, in contrast to MHC class Ia molecules, CD1d is clearly stable in the absence of beta 2m in transfected model systems and possibly in the absence of antigen, raising the possibility for other immunoregulatory functions of CD1d (Ref. 2; R. S. Blumberg, J. Garcia, H. Kim, D. Gerdes, S. Porcelli, M. Exley, and S. P. Balk, unpublished results). This may be especially relevant to CD1d function in epithelial cells. In IECs, CD1d transcription occurs within the lower zones of the crypt epithelium, with protein expression predominantly on IECs within the upper crypts and villi (26). Moreover, IEC CD1d is expressed independently of beta 2m and carbohydrate side chain modification (2) and recognized by CD8+ T cells (31). Fully glycosylated, beta 2m-associated CD1d appears to be a ligand for an invariant TCR-alpha chain expressed on double-negative human T cells bearing NKR-P1A, a KIR (15). On CD1d ligation, these double-negative T cells secrete high quantities of interferon-gamma and interleukin-4, suggesting an important immunoregulatory function. Whether epithelial cell CD1d performs a similar immunoregulatory function for local T cells, functions in the sampling of luminal bacterial antigens for presentation to local T cells, or performs another function remains to be established (6).

FcRn was originally defined as the rat receptor expressed by neonatal IECs responsible for vectorial transport of maternal IgG into neonatal animals (25). Recent studies with beta 2m knockout mice support the role of FcRn in similar functions in mice, confirm the prerequisite role of beta 2m association for FcRn function, and support the role of FcRn in regulating IgG catabolism through protection of IgG in an endocytic cycling pathway involving endothelial cells, which also express FcRn. To accomplish these functions, FcRn has maintained the basic MHC class I structure with some embellishments. Due primarily to a proline residue at position 162 in the alpha 2 domain, the potential antigen-binding groove of FcRn is disabled so that binding to its ligand, the Fc portion of IgG, occurs on the outer face of the alpha -helices. Interactions between FcRn and IgG are pH dependent (binding at acidic pH, dissociation at neutral pH) due to charged residues at the contact sites of FcRn and the hinge region of IgG. As a result, binding and transport occur at acidic pH, the pH of the neonatal lumen and endosomes, and release occurs at neutral pH, the pH of tissue and plasma. In humans, such structural properties are useful to the syncytiotrophoblast of the placenta, which is responsible for passive acquisition of maternal IgG by the fetus and from which FcRn has recently been identified. However, the functional role of FcRn expression on epithelia during adult rodent life (9) and, especially, the high-level FcRn expression in adult human intestinal epithelium (23) are not clear.

The trophoblastic epithelium of human placenta, which is in direct contact with maternal tissues, lacks classical MHC class I and class II (HLA-DR, HLA-DP, and HLA-DQ) proteins, making it susceptible to lysis by maternal NK cells, which are present in large numbers in human decidua. This problem may be remedied by the expression of HLA-G on the syncytiotrophoblast. Although considered a nonclassical MHC class I molecule linked to the MHC locus on chromosome 6, HLA-G exhibits a limited amount of allelic polymorphism in the alpha 1 and alpha 2 domains, exhibits prerequisite dependency on beta 2m, and contains alpha 1 and alpha 2 domains that fold into a groove competent to bind nonameric peptides (28, 39). Recent evidence also suggests that HLA-G is a relatively public receptor for KIRs specific for HLA-C (34). Given the possibility that HLA-G is more widely expressed than originally believed, including perhaps on other epithelial surfaces, it should be considered that these mechanisms of NK inhibition may be more generally applicable.

MICA is a recently described MHC-linked class Ib molecule that appears to exhibit relatively restricted expression to intestinal epithelium and, similar to CD1d, is somewhat indifferent to beta 2m for cell surface expression (1, 19). Although the function of MICA remains unknown, a clue may be provided by the promotor region, which exhibits functional heat shock response elements (19). This suggests a possible functional role for MICA as a cell surface flag that provides a danger signal as a consequence of some ubiquitous stress signal. This would indicate that local T cells expressing ligands for MICA may possibly be responsible for eliciting a cellular response to epithelial cell injury.

Finally, the newest member of the MHC class Ib group relevant to epithelial biology is the recently described HLA-H gene product, which has recently been renamed Hfe (16). The Hfe gene product is widely expressed through the gastrointestinal epithelium, with most prominent expression in the crypts of the small intestine (33). Mutations of this protein have been linked to the iron overload disorder hemochromatosis. Almost all hemochromatosis subjects manifest a cystine 282 right-arrow tyrosine (C282Y) mutation that disrupts association of Hfe with beta 2m and, consequently, cell surface expression of this molecule (17). Of note, the Hfe gene also contains iron response elements. The specific relationship of this allelic variant to iron transport is unknown but may lie through intermolecular associations with recently described iron transporters. These iron transporters are multiple membrane spanners (20). Interestingly, similar molecules, such as CD82, have been shown to coassociate with MHC class Ia molecules (27). This raises the possibility that these newly described iron transporters may coassociate with Hfe/beta 2m to somehow regulate intracellular iron levels. The specific ligand of Hfe remains to be determined, and its crystal structure is presently unknown.

In summary, the MHC class I protein structure contains a significant amount of information useful in accomplishing a variety of cellular tasks commonly performed by epithelial cells, specifically in areas of cellular transport (Hfe, FcRn) and regulation of lymphocyte responses to altered epithelial cells (HLA-G, MICA?) and possibly bacterial antigens (CD1). What is unique about the MHC class I-like structure that makes it useful to epithelial cells? It can only be conjectured that its value lies in the ability of these molecules to link specific ligand binding to a variety of hardwired cellular pathways involved in protein trafficking that ultimately result in regulating lymphocyte responses. There is an enormous amount of work still to be done to elucidate the functional mechanisms of these and other yet to be discovered MHC class Ib molecules in epithelial cell biology.

    ACKNOWLEDGEMENTS

This study was supported by National Institutes of Health Grants DK-44319, AI-53056, and DK-51362 and by a grant from the Crohn's and Colitis Foundation of America.

    FOOTNOTES

* Second in a series of invited articles on Current Concepts in Mucosal Immunity.

Address reprint requests to Gastroenterology Division, Brigham and Women's Hospital, 75 Francis St., Thorn 1410, Boston, MA 02115.

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