HLA-DMA and -DMB genes are both required for MHC class II/peptide complex formation in antigen-presenting cells

Fling, Steven P.; Arp, Benjamin; Pious, Donald

doi:10.1038/368554a0

Cited by 266 publications

(94 citation statements)

References 26 publications

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“…The recent findings that amino-terminal fragments of Ii may prevent peptide loading in the ER (33,34) do not preclude this model. The ability of p12 to facilitate class II peptide loading might be affected by several variables-for example, the low pH found in the endosomal compartment, the exact point of truncation at the carboxyl terminus of the naturally processed p12, or the participation of other chaperone molecules such as HLA-DM, a major histocompatibility complexlinked protein involved in antigen presentation, but of yet unknown specific function (44)(45)(46)(47)(48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

Proteolysis of major histocompatibility complex class II-associated invariant chain is regulated by the alternatively spliced gene product, p41.

Fineschi

Arneson

Naujokas

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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Invariant chain (Ii) is an intracellular type II transmembrane glycoprotein that is associated with major histocompatibility complex class II molecules during biosynthesis. Ii (5,7,8).Once the class 11-Ii complexes arrive in endosomes, Ii appears to be degraded through the generation of a nested set of amino-terminal fragments, some of which remain transiently associated with class II (9-11). The ability of Ii to enhance the localization of class II to endosomes has been mapped predominantly to a region in the amino-terminal cytoplasmic domain that contains an endosomal retention and/or localization signal (6)(7)(8)(12)(13)(14)(15)(16)(17). Recently, the carboxyl-terminal segment of the cytosolic domain of Ii (18) 10257The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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Section: Discussionmentioning

confidence: 99%

Proteolysis of major histocompatibility complex class II-associated invariant chain is regulated by the alternatively spliced gene product, p41.

Fineschi

Arneson

Naujokas

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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“…The epitope recognized by the 16.23 mAb depends upon DR3 molecules acquiring a mature conformation, and is lost in DM-negative B-LCL (10,11,31,32) as illustrated for T2-DR3 in Fig. 2Bb.…”

Section: M1 Cells Do Not Constitutively Express Dr II or Hla-dm Molmentioning

confidence: 99%

“…An endosomal targeting motif within the amino terminus of the p33 form of Ii directs the Ii-class II complexes to specialized endosomal compartments, MIIC (6,7). Here, Ii is sequentially degraded by proteases, and the catalytic activity of HLA-DM promotes exchange of CLIP for peptides derived from endocytosed proteins (8)(9)(10)(11).…”

mentioning

confidence: 99%

In the absence of the invariant chain, HLA-DR molecules display a distinct array of peptides which is influenced by the presence or absence of HLA-DM

Lightstone¹,

Hargreaves²,

Bobek³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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The independent inf luences of invariant chain (Ii) and HLA-DM molecules on the array of naturally processed peptides displayed by HLA-DR molecules were studied using transfected cell lines. Major histocompatibility complex (MHC) class II molecules present peptide antigens to MHC class II-restricted CD4 ϩ T cells. The peptides presented are usually derived from internalized exogenous or membrane-bound proteins (1) which are unfolded, denatured, and degraded within the progressively acidic endosomal pathway. Class II molecules are assembled in the endoplasmic reticulum (ER), where they associate noncovalently with the invariant chain (Ii), a type 2 transmembrane protein (reviewed in ref.2). The CLIP region of Ii (amino acids 81-104) binds in the groove of nascent MHC class II molecules, thereby inhibiting the binding of peptides in the ER (3-5). An endosomal targeting motif within the amino terminus of the p33 form of Ii directs the Ii-class II complexes to specialized endosomal compartments, MIIC (6, 7). Here, Ii is sequentially degraded by proteases, and the catalytic activity of HLA-DM promotes exchange of CLIP for peptides derived from endocytosed proteins (8-11).In the absence of Ii, as shown in Ii knockout mice (Ii 0/0 ), few class II molecules reach the cell surface, as most are retained in the ER and degraded (12, 13). The studies of antigen presentation by Ii-negative (Ii Ϫ ) cells reported to date have largely used T cell clones or hybridomas raised against conventional antigen-presenting cells (APC) as responders. The results of such studies have shown that a degree of overlap exists between the peptides displayed by MHC class II molecules expressed in the presence and the absence of Ii (for example, see ref. 14). However, this approach does not inform whether the complete or relative absence of Ii leads to the display of novel peptide epitopes by MHC class II molecules, an important issue if circumstances can arise in vivo in which Ii is limiting in MHC class II ϩ cells.In this study we used alloreactive T cell clones as probes of peptide occupancy of class II molecules expressed in the presence or absence of Ii and HLA-DM on the basis that anti-MHC allorecognition generally involves the corecognition of the allogeneic MHC molecule and bound peptide (for review see ref. 15). The results suggest that in the absence of Ii, MHC class II molecules display a distinct array of peptides. Furthermore, HLA-DM influenced allorecognition of DR molecules in the absence of Ii, suggesting that HLA-DM can influence MHC class II peptide occupancy independently of Ii. Taken together, these findings support the prediction that discordant regulation of MHC class II, Ii, and HLA-DM molecules in vivo, as has been observed in bone marrow macrophages (16) and in gut epithelial cells (17) for MHC and Ii, could lead to the display of self-peptides to which the T cell repertoire is not tolerant.

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“…Here, Ii is degraded, leaving Ii-derived peptides in the antigen binding groove (class II-associated Ii peptides, CLIP). CLIP must be released from class II molecules to permit normal binding of endosomal peptides, a process that is accelerated by HLA-DM (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). In addition, DM-catalyzed peptide release is not limited to CLIP (15,18,19), so that distinct sets of peptides are loaded onto class II molecules in DM ϩ and DM Ϫ cells (20,21).…”

Section: Major Histocompatibility Complex (Mhc)mentioning

confidence: 99%

Secondary Structure Composition and pH-dependent Conformational Changes of Soluble Recombinant HLA-DM

Busch¹,

Reich²,

Zaller³

et al. 1998

Journal of Biological Chemistry

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HLA-DM catalyzes the release of invariant chain fragments from newly synthesized major histocompatibility complex (MHC) class II molecules, stabilizes empty class II molecules, and edits class II-associated peptides by preferentially releasing those that are loosely bound. The ability of HLA-DM to carry out these functions in vitro is pH dependent, with an optimum at pH 4.5-5.5 and poor activity at pH 7. The structural basis for these properties of HLA-DM is unknown. Sequence homology suggests that HLA-DM resembles classical, peptidebinding MHC class II molecules. In this study, we examined whether HLA-DM has a secondary structure composition consistent with an MHC fold and whether HLA-DM changes conformation between pH 5 and pH 7. Far-UV circular dichroism (CD) spectra of recombinant soluble HLA-DM (sDM) indicate that HLA-DM belongs to the ␣/␤ class of proteins and structurally resembles both MHC class I and class II molecules. The CD peak around 198 nm increases upon going from neutral to endosomal pH and drops sharply upon denaturation below pH 3.5, distinguishing at least three states of sDM: the denatured state and two highly similar folded states. Fluorescence emission spectra show a slight blue-shift and a Ϸ20% drop in intensity at pH 5 compared with pH 7. Unfolding experiments using guanidinium chloride show that the stability of sDM is somewhat reduced but not lost at pH 5. These results indicate that sDM undergoes a pH-dependent conformational change between neutral and endosomal pH. The change seems to involve both hydrogen bonding patterns and the hydrophobic core of sDM and may contribute to the pH dependence of DM activity. Major histocompatibility complex (MHC)1 encoded glycoproteins bind antigenic peptides and display them on the surface of antigen-presenting cells for inspection by T lymphocytes bearing ␣␤ antigen receptors. MHC molecules can be divided into class I and class II molecules, which share a common tertiary fold with a characteristic peptide binding groove but differ in their domain connectivity, specificity requirements for peptide, and ability to stimulate selectively CD8 ϩ and CD4 ϩ lymphocytes, respectively (1). These highly polymorphic "classical" MHC molecules belong to a larger family, which includes more distantly related and less polymorphic molecules encoded in the class II and class Ib regions of the MHC and elsewhere in the genome (2). Among the functions identified for such "nonclassical" MHC molecules are antigen presentation to unconventional T cells, accessory functions in MHC class II antigen presentation, and other, unrelated functions. Classical MHC class II molecules load peptides in endosomal compartments, and this process is regulated by at least three additional molecules: invariant chain (Ii), HLA-DM, and HLA-DO (3, 4). Ii, which lacks homology to MHC molecules, associates with class II molecules in the endoplasmic reticulum, facilitates their assembly, and targets them to endosomes. Here, Ii is degraded, leaving Ii-derived peptides in the antigen binding groo...

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HLA-DMA and -DMB genes are both required for MHC class II/peptide complex formation in antigen-presenting cells

Cited by 266 publications

References 26 publications

Proteolysis of major histocompatibility complex class II-associated invariant chain is regulated by the alternatively spliced gene product, p41.

Proteolysis of major histocompatibility complex class II-associated invariant chain is regulated by the alternatively spliced gene product, p41.

In the absence of the invariant chain, HLA-DR molecules display a distinct array of peptides which is influenced by the presence or absence of HLA-DM

Secondary Structure Composition and pH-dependent Conformational Changes of Soluble Recombinant HLA-DM

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