(The FASEB Journal. 2002;16:202-206.)
© 2002 FASEB
MHC and MHC-related proteins as pleiotropic signal molecules
DAVID M. OJCIUS*,
CHRISTIANE DELARBRE
,
PHILIPPE KOURILSKY and
GABRIEL GACHELIN1
Unité de Biologie Moléculaire du Gène de l’Institut Pasteur,
* Université Paris 7, and
INSERM U277, Institut Pasteur, 75724 Paris cedex 15, France
1Correspondence: Unité de Biologie Moléculaire du Gène, Institut Pasteur, 25 rue du Dr. Roux, 75015 Paris. E-mail: ggachel{at}pasteur.fr
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ABSTRACT
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Class I molecules of the major histocompatibility complex (MHC) have been studied primarily for their role in presenting peptide antigens to conventional T lymphocytes. An increasing body of evidence suggests that MHC and newly characterized MHC-related molecules have a much more varied function in the body. Many of these molecules are involved in pleiotropic interactions with other proteins, which initiate signal transduction cascades and contribute to cellular and tissue homeostasis.—Ojcius, D. M., Delarbre, C., Kourilsky, P., Gachelin, G. MHC and MHC-related proteins as pleiotropic signal molecules.
Key Words: signal transduction • homeostasis • protein–protein interaction • MHC class I
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INTRODUCTION
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THE POLYMORPHIC (CLASS Ia) major histocompatibility complex (MHC) molecules are known mostly for their role in presenting peptide antigens to antigen-specific cytotoxic T cells and thus for their role in defense against infections. However, in addition to defining the class Ia peptide complexes recognized by specific T cell receptor (TCR) of CD8+ T cells, the peptide cargo stabilizes class I molecules. Properly folded molecules can subsequently interact with activating and inhibitory natural killer (NK) receptors cells in a manner that is largely independent of the nature of their peptide cargo. Evidence for an increasing diversity of functions associated with class I molecules has come from the diverse and expanding universe of MHC class Ib genes and MHC class I-related proteins located outside of the MHC. Current studies are revealing strikingly different molecular structures, interactions, and biological functions for some class Ib and class I-related molecules. Some, such as class Ia, carry a highly diverse cargo of antigenic peptides, whereas others present subsets of molecules of limited diversity or harbor no cargo at all. The binding partners of class I molecules also extend far beyond TCR molecules. Recent publications suggest that class I molecules may be pleiotropic ligands that transfer information between different biological systems and control cell activity. Specific antigen presentation, followed by clonal T cell recognition, may be a more specialized function for some class I, particularly class Ia, molecules.
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VARIETY OF RECEPTORS FOR SOME CLASS Ib PROTEINS
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Most receptors of MHC molecules studied belong to the 
ß TCR family. The details of the interaction between several TCR/peptide class Ia complexes suggest that clonal recognition and expansion may be the rule. Few studies, however, have been carried out on populations of T cells restricted by a given class Ib or class I-related molecule, and the results obtained so far tend to favor broad and polyclonal, rather than specific, antigen recognition. The best-documented example concerns the CD4+ and double-negative (DN) T cells that use the invariant V14-J281 TCR in mice or V24-JQ in humans, which are restricted in both species by CD1d. No CD8+ T cells using similar TCR have been detected to date. In contrast to human CD1a, b, and c, which direct conventional T cell responses against the carbohydrate moiety of glycolipids, murine and human CD1d, although capable of binding self and nonself glycolipids, do not appear to direct antigen-specific responses (Table 1
). Recent reports on the repertoire of CD1d-restricted T cells (1)
as well as the detection of murine and human CD1d-restricted T cells with CD1d tetramers loaded with -galactosyl ceramide (2)
have led to the conclusion that most of these ‘CD1d-imprinted clones’, although displaying the markers of activated/memory cells, are polyclonal, with no evidence for the clonal expansions characteristic of antigen-driven proliferation. The physiological cargo of CD1d is not known, but one could speculate that the TCR invariant chain may react predominantly with the CD1d molecule itself in an autoreactive manner instead of detecting molecular details of the antigens presented.
Class Ia molecules able to bind peptides may present a set of peptides of very limited diversity. Some of these peptides must be considered in the context of host defense against infections. As an example, the class Ib molecule H2-M3 presents to T cells only short peptides whose sequence begins with an N-formyl-methionine, thus limiting the presentation to peptides derived from either mitochondrial or bacterial proteins. Either of these may in turn lead to a cytotoxic response or behave as chemotactic factors. It is worth noting that H2-M3 and its structural equivalents have been detected only in rodents. Functional equivalents may exist, however, as for other class I molecules (see below). Some MHC-Ib molecules, such as Qa-1 or HLA-E, present peptides of limited diversity such as peptides derived from the leader sequence of distinct class Ia proteins (Table 1)
. The resulting complexes are recognized by T cells, but are used mostly for the control of NK (and presumably NKT) activity through their interaction with CD94/NKG2 A, C, E, and D receptors (see below).
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ENZYMATIC ACTIVITIES ASSOCIATED WITH CLASS I-RELATED MOLECULES
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Akin to the specificity observed in enzyme–substrate interactions, the mono- or oligomorphism of class Ib and class I-related molecules may be required for binding to unconventional receptors, which may include substrates of enzymatic reactions or non-TCR macromolecules. A major signal for the weight loss observed during many types of cancer is the class I-related molecule Zn-2-glycoprotein (ZAG). This soluble protein is secreted by the liver, is present in body fluids, and is overexpressed in tumors. ZAG does not appear to have enzymatic activity itself, but most likely binds to an as-yet-unidentified ß-adrenergic receptor that stimulates adenylate cyclase through a GTP-dependent pathway, similar to the action of lipolytic hormones. Despite the absence of ß2-microglobulin, the structure of ZAG resembles the class I heavy chain (3)
; the ligand binding groove carries a cargo—a protease-resistant compound that might be a lipid. Nonetheless, an immunological role for ZAG remains to be demonstrated, and its action appears to be that of a signal molecule controlling the activity of target cells.
Other class Ib and class I-related molecules such as HFE (which modulates iron internalization via the transferrin receptor) and the neonatal Fc receptor (which transports IgG across intestinal epithelia and kidney tubules) do not bind peptides. Instead, they transport macromolecules between different cellular or body compartments. Other soluble class Ib and class I-related proteins also exist, including Q10, Qa-2, and HLA-G (Table 1)
. No function has been identified for these proteins but, like ZAG, they may function in an endocrine fashion to stimulate metabolism in distant tissues or have an unknown role transmitting ligands or signals to other parts of the organism.
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STRESS SIGNALING VIA CLASS Ib MOLECULES
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MICA/B may represent the clearest known example of molecules that herald cellular transformation or the presence of intracellular microbial infection. MICA/B interacts with NKG2D on human NK cells, 
T cells, and CD8+ ß T cells (Table 1)
. On cells infected by the cytomegalovirus (CMV), increased cell surface expression of MICA/B led to costimulation of CD8+ ß T cells by NKG2D engagement and strongly enhanced TCR-dependent cytolytic responses by CMV-specific ß T cells (4)
. In cells infected by Mycobacterium tuberculosis, overexpression of MICA led to a large enhancement of the TCR dependent V2V2 T cell response (5)
. In the intestine, MICA/B-expressing target cells are recognized by intraepithelial lymphocytes, resulting in target cell lysis. MICA/B are membrane bound; however, the MICA/B 1-2 platform is inverted in such a way that the underside of the ß-sheet floor may be accessible to effector cells whereas the putative peptide binding groove faces the MICA/B-expressing cell, suggesting that effector cells recognizing MICA/B may do so in a markedly different way from ß T cells (6)
.
T22/T10-specific T cells have been identified in the mouse, and expression of T22/T10 is increased during activation with LPS or concanavalin A (7
; Table 1
). These T cells may therefore sense the expression of T22/T10 under different pathological conditions. T22b assumes an overall MHC-like fold, but one side of the groove normally used in peptide binding is truncated, and two acidic patches on the exposed ß-sheet floor have been proposed as potential interaction sites for TCR (8)
. Compared with interaction between ß TCR and class Ia peptide complexes, the binding affinity of T22 for TCR is very high, again consistent with TCR behaving differently from ß TCR.
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REGULATION OF NK CELL ACTIVITY THROUGH LIGATION OF NKG2 RECEPTORS
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NKG2 receptors represent distinct families of membrane-bound molecules that were first identified on the surface of NK cells. They consist of activating molecules (NKG2D and NKG2C/E) and inhibitory molecules (NKG2A/B). Some of these receptors have been found on other cell types, which implies that interactions with these receptors extend beyond the control of NK cell activity.
NKG2D interacts not only with MICA/B in humans, but also with the distantly related MHC molecules ULBP, which are not thought to present peptides (9)
. The functional equivalents of MICA/B in mice are the retinoic acid-inducible Rae-1 and the minor histocompatibility molecule H-60, which render cell lines and tumors susceptible to NK-mediated killing (10
11
12)
. As in the case of MICA/B, no cargo has been identified for Rae-1. Their regulatory function may thus require protein–protein interactions rather than antigen presentation.
The murine class Ib molecule Qa-1 is encoded by the T23b gene and is the functional equivalent of HLA-E (13
; Table 1
). Qa-1 engagement of CD94-NKG2C leads to activation, whereas interaction with CD94-NKG2A results in inhibition. Qa-1 may be loaded with a promiscuous set of hydrophobic peptides, but the dominant peptides are derived from class Ia leader sequences. Differences in the chemical nature of the cargo may play a role in the interactions between Qa-1/HLA-E and different members of the NKG2 family (14)
.
Some class I-related genes are involved in the control of NK cell activity by cancer cells and virally infected cells. Of particular interest is the virally encoded CMV protein UL16, which assumes the same overall structure as class Ia proteins and blocks the cytotoxicity of NK cells by masking NKG2D-dependent NK cell recognition of ULBP or MICA/B (9)
.
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SIGNALING IN THE CENTRAL NERVOUS SYSTEM VIA MHC MOLECULES
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Recently published data show that class Ia and class Ib molecules play a role in establishing proper connections within the central nervous system (CNS). It has long been assumed that MHC class I molecules are not expressed by cells of the CNS. However, not only are class I molecules expressed in well-defined structures such as the laterate geniculate nucleus (LGN) and hippocampus, but the expression of MHC molecules and ß2-microglobulin is modulated by the electrical activity of neurons. In the neonatal cat brain, visual activity controls class I expression in the LGN during remodeling of axon termination. In the mature hippocampus, the expression of class I molecules is enhanced by epileptic seizure (15)
. These observations have been extended to mice, where a deficiency in class I molecules or the CD3
chain leads to incomplete maturation of retino-tectal connections. Moreover, the few MHC class I genes tested (K, D, Qa-1, and T22) had different patterns of expression in the mature CNS, particularly in the neocortical layers, with Qa-1 being expressed in layer 6, T-22 in layers 5 and 6, H-2D in layer 4, and H-2K not detectable (16)
. The expression of class I genes during development, as well as their role in neurons that undergo activity-dependent changes and plasticity, reflects an electrical activity-controlled regulatory pathway that has little in common with the usual immune functions of MHC. The role of CD3 is unclear, and the identity of the MHC receptor, which may fulfill either an immune or a nonimmune function, is not known. In relation to the CNS, it is worthwhile recalling that MHC molecules contribute to mating behavior in mice.
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CONCLUDING REMARKS
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Many MHC molecules have been identified by genomic analysis. It is likely that, as for Rae-1 and H-60, other genes too distantly related by sequence to be identified using traditional algorithms will be discovered in the future. Some of the class Ib and class I-related molecules, such as the neonatal Fc receptor and the transferrin coreceptor HFE, have known functions. They do not carry antigenic cargo and act as transporters of macromolecules. Others have suspected functions, such as H2-M3, which binds N-formylated Met peptides of mitochondrial or bacterial origin. Although H2-M3 molecules, like other class Ib proteins, are synthesized and loaded in the endoplasmic reticulum with endogenous peptides, there is little surface expression of H2-M3 in uninfected cells due to a scarcity of endogenous N-formylated peptides. After bacterial infection, empty H2-M3 molecules that had been retained in the endoplasmic reticulum are rapidly loaded with bacterial N-formylated peptides, some of which may be internalized through an endosomal/lysosomal pathway (17)
. Other identified genes have no known function despite their ubiquitous expression (such as for MR1) or the large number of their genes )as for the H2-M10 family).
These studies confirm the view that class I molecules interact directly with a multiplicity of proteins that are present on a variety of cell types. A likely scenario is that most class Ib and class I-related molecules regulate cell-to-cell-contact or transmit signals to other parts of the organism even if some of them may also present antigens. The class Ia molecules themselves exhibit dual function, activating CD8+ cells while at the same time inhibiting NK cells. The general role of class I genes may thus be to control cell activity, with antigen-specific cytotoxicity being a specific example of how they contribute to homeostasis.
Genetic studies of the MHC of vertebrates have always shown the existence of polymorphic genes (genes with a high frequency of alleles whose polymorphism is primarily due to gene conversion) and mono- and oligomorphic genes, which have little allelic diversity and whose discrete polymorphism is spread throughout the length of the genes. Some of the monomorphic genes are donor genes for gene conversion, and thus contribute to the diversity of the polymorphic genes. The monomorphic genes are not only donor sequences, however. They are themselves subject to unequal recombination events, leading to marked variation in the number of class Ib genes among species and even strains, a striking feature that has long been difficult to reconcile with the precise function of most class Ib gene products. The basis for the clear-cut dichotomy between polymorphic and monomorphic genes has never been clearly explained.
In view of the emerging role for class Ib molecules, an alternative explanation may be proposed. Two very different selective pressures can be identified as acting on MHC class I genes: one focused on increasing the diversity of antigen presentation and one on preservation of protein/protein interactions. If one considers that the goal of the polymorphic genes is to maximize their allelic diversity and thus their ability to present the highest possible number of different antigens, then one may propose that the limited diversity of mono- and oligomorphic genes within a species is imposed by the fact that the encoded proteins have to interact with other equally invariant or relatively invariant proteins. The absence of allelic polymorphism of class Ib molecules may be a condition for their ability to transfer information, as the limited allelic diversity of class Ib molecules would place constraints on interactions with a set of receptors of limited allelic diversity.
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ACKNOWLEDGMENTS
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This work was supported by the Pasteur Institute, INSERM, and Université Paris 7.
Received for publication September 27, 2001.
Accepted for publication October 18, 2001.
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ABSTRACT
INTRODUCTION
