Synthesis and expression of MHC class II molecules in the absence of attached invariant chains by recombinant interferon‐γ‐activated bone marrow‐derived macrophages

Schneider, Franz-Josef; Opel, Beate; Ballhausen, Wolfgang G.; Henkes, Wolfgang; Steinlein, Peter; Reske, Konrad

doi:10.1002/eji.1830170904

Cited by 17 publications

(20 citation statements)

References 50 publications

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“…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.…”

supporting

confidence: 86%

“…M1 demonstrates clear discordant regulation of HLA-DM, Ii, and class II gene expression. Up-regulation of class II molecules but not Ii has been reported in bone marrow macrophages (16) and in gut epithelial cells (17). Limited comparisons have been made of the levels of induction of MHC class II, Ii, and HLA-DM in specialized APC and in other cell types in which MHC class II molecule expression is induced by agents such as IFN␥.…”

Section: Discussionmentioning

confidence: 99%

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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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supporting

confidence: 86%

Section: Discussionmentioning

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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“…Indeed, early classification of the different strains of S. aureus suggested that TSST-1 expression is over-represented in strains targeting the blood compartment, as compared with SEB whose expression is more restricted to strains invading the gastrointestinal tract (28). Accordingly, our results suggest that TSST-1, in contrast to SEB, would bind and be presented much more efficiently by fully functional APCs as opposed to cells physiologically expressing low levels of Ii and DM (29,30). An intestinal pathogen could possibly gain a selective advantage by expressing a given SAg rather than another and this heterogeneity may well be functionally exploited by bacteria encoding these SAgs.…”

Section: Discussionmentioning

confidence: 66%

Selective binding of bacterial toxins to major histocompatibility complex class II-expressing cells is controlled by invariant chain and HLA-DM

Lavoie

Thibodeau

Cloutier

et al. 1997

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

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Bacterial superantigens (SAgs) bind to major histocompatibility complex (MHC) class II molecules and activate T cells in a V␤-restricted fashion. We recently identified subsets of HLA-DR1 molecules that show selectivity for SAgs. Here, we extend these observations by showing that different cell lineages demonstrate distinct SAg-binding specificities although they all express HLA-DR1. Indeed, B cells bind staphylococcal enterotoxin A (SEA) and toxic shock syndrome toxin 1 (TSST-1) with high affinity while staphylococcal enterotoxin B (SEB) binding is barely detectable. In contrast, DR1-transfected HeLa cells show efficient binding of SEB, but not of SEA or TSST-1. We investigated the class II maturation events required for efficient interaction with SAgs and found that the ability of cells to bind and present the toxins can be drastically modulated by coexpression of the class II-associated invariant chain (Ii) and HLA-DM. SEA binding to DR1 molecules required coexpression of Ii, whereas TSST-1 binding was selectively enhanced by DM. Binding of SEB was affected by cell type-specific factors other than Ii or DM. The selectivity of SAgs for different MHC class II populations was minimally affected by HLA-DR intrinsic polymorphism and could not be explained by binding to alternative sites on DR molecules. Our results indicate that SAgs are sensitive to structural heterogeneity in class II molecules, which is consequent to the differential regulation of expression of antigen processing cofactors. Therefore, we speculate that Staphylococcus aureus have retained the ability to express numerous SAgs in adaptation to the microheterogeneity displayed by MHC class II molecules and that this may relate to their ability to infect different tissues.

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“…[32][33][34][35] Consistent with our observations, invariant chain-independent class II expression on the cell surface was seen in DCs and activated macrophages, but not in B cells. 36,37 The presentation of MHC class I and class II chicken ovalbumin (OVA) epitopes is shown in Figure 2. C75BL/6 (H-2 b ) mice present an H-2K b class I-restricted dominant epitope and an I-A brestricted class II dominant epitope.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of invariant chain expression in dendritic cells presenting endogenous antigens stimulates CD4+ T-cell responses and tumor immunity

Zhao

Boczkowski

Nair

et al. 2003

Blood

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Induction of potent and sustained antiviral or antitumor immunity is dependent on the efficient activation of CD8+ and CD4+ T cells. While dendritic cells constitute a powerful platform for stimulating cellular immunity, presentation of endogenous antigens by dendritic cells transfected with nucleic acid-encoded antigens favors the stimulation of CD8+ T cells over that of CD4+ T cells. A short incubation of mRNA-transfected dendritic cells with antisense oligonucleotides directed against the invariant chain enhances the presentation of mRNA-encoded class II epitopes and activation of CD4+ T-cell responses in vitro and in vivo. Immunization of mice with the antisense oligonucleotide-treated dendritic cells stimulates a more potent and longer lasting CD8+ cytotoxic T-cell (CTL) response and enhances the antitumor efficacy of dendritic cell-based tumor vaccination protocols. Transient inhibition of invariant chain expression represents a simple and general method to enhance the stimulation of CD4+ T-cell responses from endogenous antigens. (Blood. 2003;102:4137-4142)

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Synthesis and expression of MHC class II molecules in the absence of attached invariant chains by recombinant interferon‐γ‐activated bone marrow‐derived macrophages

Cited by 17 publications

References 50 publications

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

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

Selective binding of bacterial toxins to major histocompatibility complex class II-expressing cells is controlled by invariant chain and HLA-DM

Inhibition of invariant chain expression in dendritic cells presenting endogenous antigens stimulates CD4+ T-cell responses and tumor immunity

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