The Role of β
            <sub>2</sub>
            -Microglobulin in Peptide Binding by Class I Molecules

Vitiello, Antonella; Potter, Terry A.; Sherman, Linda A.

doi:10.1126/science.2124002

Cited by 174 publications

(99 citation statements)

References 37 publications

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“…It was subsequently shown to be the noncovalently bound L chain of highly polymorphic MHC class I molecules (2). In these membrane glycoproteins, which present peptide Ags to CTLs (3) and regulate NK cells (4), ␤ 2 m forms a central part of the structure, one necessary for the proper folding and cell surface display of the class I molecule (5)(6)(7)(8). Many different loci encode class I H chain genes and only some of them are located in the MHC (9).…”

mentioning

confidence: 99%

The β2-Microglobulin Locus of Rainbow Trout (Oncorhynchus mykiss) Contains Three Polymorphic Genes

Magor

Shum

Parham

2004

The Journal of Immunology

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β2-microglobulin (β2m) associates with MHC and related class I H chains to form cell surface glycoproteins that mediate a variety of functions in defense. In humans, monomorphism of a single β2m gene contrasts with the diversity and polymorphism of the class I H chain genes, and a similar picture was seen in almost all other species examined. In this regard, rainbow trout (Oncorhynchus mykiss) appeared unusual: trout β2m genes gave a complicated and polymorphic pattern in Southern blots, and a minimum of 10 different mRNA encoding two distinct types of β2m were expressed by a single fish. Characterization of genomic clones from the same fish now shows that the rainbow trout β2m locus consists of two expressed genes and one partial gene that are closely linked. Four copies of the locus were identified and allelic variants of each gene defined, largely through comparison of the noncoding regions. A dramatic variation in the lengths of introns is caused by variable repetitive elements and accounts for the complex pattern seen in Southern blots. By comparison to noncoding sequences, the coding regions are conserved but the three loci differ within a cluster of codons that encode residues of β2m that do not interact with class I H chains. Additional diversity in the trout β2m genes appears to be due to somatic mutation that might be facilitated by the abundance of repetitive DNA elements within the 12 β2m genes of an individual rainbow trout.

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confidence: 99%

The β2-Microglobulin Locus of Rainbow Trout (Oncorhynchus mykiss) Contains Three Polymorphic Genes

Magor

Shum

Parham

2004

The Journal of Immunology

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“…All of these approaches attempt to introduce peptide into the endogenous loading pathway. Alternatively, direct cell surface loading of MHC I molecules in vitro has also been demonstrated but is inefficient in the absence of serum (22,23). Thus, peptide antigens can be bound to MHC I molecules, but they must either be introduced into the endogenous pathway or be loaded exogenously.…”

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confidence: 99%

The Effect of Human β2-Microglobulin on Major Histocompatibility Complex I Peptide Loading and the Engineering of a High Affinity Variant

Shields¹,

Kubota²,

Hodgson³

et al. 1998

Journal of Biological Chemistry

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The ability to directly load cell surface major histocompatibility complex (MHC) class I molecules with peptides provides a potentially powerful approach toward the development of vaccines to generate cell-mediated immunity. We demonstrate that exogenous ␤ 2 -microglobulin (␤ 2 m) stabilizes human cell surface MHC I molecules and facilitates their loading with exogenous peptides. Additionally, using three-dimensional crystal structures and known interaction sites between MHC I heavy chains and ␤ 2 m, we engineered variants of human ␤ 2 m (h␤ 2 m) with a single serine substitution at residue 55. This alteration was predicted to promote hydrophobic interactions at the MHC I heavy chain/␤ 2 m interface and displace an ordered water molecule. Compared with h␤ 2 m, the serine to valine substitution at residue 55 had improved ability to bind to cell surface HLA-A1, HLA-A2, and HLA-A3 molecules, facilitate exogenous peptide loading, and promote recognition by peptide-specific T cells. The inclusion of h␤ 2 m or higher affinity variants when pulsing cells with MHC-restricted peptides increases the efficiency of peptide loading 50 -80-fold. Therefore, the inclusion of h␤ 2 m in peptide-based vaccines may increase cell surface antigen densities above thresholds that allow recognition of peptide antigens by the immune system, particularly for cryptic, subdominant, or marginally antigenic peptides.In the field of vaccine development, it has been relatively simple to induce humoral responses to injected antigens. However, one of the major challenges in the treatment of tumors and viral infections is the generation of vaccines that stimulate cell-mediated immune responses to these pathogens. Specific cytolytic responses are generally mediated by CD8ϩ T cell recognition of antigenic peptides in the context of major histocompatibility complex (MHC) 1 class I molecules. Recent advances in defining "supermotif" antigens capable of being presented by multiple MHC I alleles (1-4) and immunodominant epitopes (5-9) will undoubtedly have a significant impact on realizing these goals. However, beyond defining appropriate antigenic peptides, a second challenge lies in establishing effective methods with which to deliver these antigens to the MHC I loading pathway. Typically, MHC I molecules acquire peptides generated by the degradation of endogenous proteins by the proteasome. These peptides are transported into the endoplasmic reticulum, where they are bound by MHC I⅐␤ 2 -microglobulin (␤ 2 m) complexes and finally transit to the cell surface (10 -12). Although this pathway is the dominant means of loading MHC I molecules, other methods of delivering antigenic peptides to MHC I have been described including direct incorporation of DNA into cells (13-16), phagocytosis-dependent representation of antigens (17, 18), and infection by bacterial (19) or viral vectors (20, 21). All of these approaches attempt to introduce peptide into the endogenous loading pathway. Alternatively, direct cell surface loading of MHC I molecules in vitro has al...

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“…HLA class I heavy chains bind B2m more strongly than do mouse class I heavy chains, and incubation of human ceils in the presence of bovine 32m does not lead to significant 32m exchange, as is the case for mouse cells (25). In mouse cell lines that lack expression of 32m, some fraction of class I heavy chains reach the cell surface (26,27). This is also true for cells of mice rendered 02m-negative through "knock-out" of the 32m gene (28,29), for which incubation with exogenous 32m and an appropriate binding peptide can reconstitute functional class I molecules at the cell surface (30).…”

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Species-specific differences in chaperone interaction of human and mouse major histocompatibility complex class I molecules.

Nößner

Parham

1995

The Journal of Experimental Medicine

150

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SummaryPrevious studies have shown that immature mouse class I molecules transiently associate with a resident endoplasmic reticulum protein of 88 kD that has been proposed to act as a chaperone for class I assembly. Subsequently, this protein was demonstrated to be identical to calnexin and to associate with immature forms of the T cell receptor complex, immunoglobulin, and human class I HLA heavy chains. In this paper we define further the interaction of human dass I HLA heavy chains with chaperone proteins and find key differences with the complexes observed in the mouse system. First, calnexin and immunoglobulin binding protein (BiP) both associate with immature HLA class I heavy chains. The two chaperones are not found within the same molecular complex, suggesting that calnexin and BiP do not interact simultaneously with the same HLA class I heavy chain. Second, only free HLA class I heavy chains, and not 32-microglobulin (Bzm)-associated heavy chains are found associated with the chaperones. Indeed, addition of free 32m in vitro induces dissociation of chaperone-class I HLA heavy chain complexes. The kinetics for dissociation of the class I HLA heavy chain-chaperone complexes and for formation of the class I HLA heavy chain-32m complex display a reciprocity that suggests the interactions with chaperone and 32m are mutually exclusive. Mouse class I heavy chains expressed in human cells exhibit the mouse pattern of interaction with human chaperones and human 32m and not the human pattern, showing the difference in behavior is purely a function of the class I heavy chain sequence.

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The Role of β ₂ -Microglobulin in Peptide Binding by Class I Molecules

Cited by 174 publications

References 37 publications

The β2-Microglobulin Locus of Rainbow Trout (Oncorhynchus mykiss) Contains Three Polymorphic Genes

The β2-Microglobulin Locus of Rainbow Trout (Oncorhynchus mykiss) Contains Three Polymorphic Genes

The Effect of Human β2-Microglobulin on Major Histocompatibility Complex I Peptide Loading and the Engineering of a High Affinity Variant

Species-specific differences in chaperone interaction of human and mouse major histocompatibility complex class I molecules.

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The Role of β 2 -Microglobulin in Peptide Binding by Class I Molecules

Cited by 174 publications

References 37 publications

The β2-Microglobulin Locus of Rainbow Trout (Oncorhynchus mykiss) Contains Three Polymorphic Genes

The β2-Microglobulin Locus of Rainbow Trout (Oncorhynchus mykiss) Contains Three Polymorphic Genes

The Effect of Human β2-Microglobulin on Major Histocompatibility Complex I Peptide Loading and the Engineering of a High Affinity Variant

Species-specific differences in chaperone interaction of human and mouse major histocompatibility complex class I molecules.

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About

The Role of β ₂ -Microglobulin in Peptide Binding by Class I Molecules