Alloantibodies can discriminate class I major histocompatibility complex molecules associated with various endogenous peptides.

Sherman, Linda A.; Chattopadhyay, Suschmitta; Biggs, Judith A.; Dick, Robert F.; Bluestone, Jeffrey A.

doi:10.1073/pnas.90.15.6949

Cited by 38 publications

(23 citation statements)

References 26 publications

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“…This hypothesis also is not very likely. Third, HLA conformational changes induced by peptides may alter serological epitopes and inhibit mAb recognition (6)(7)(8)(9)(10)(11)(12)(13)28). Previous crystallographic analysis of HLA-A2, -B8, and -A11 molecules have shown subtle structural differences when various peptides are introduced in the binding groove (20,22,29).…”

Section: Discussionmentioning

confidence: 99%

“…This effect has been mainly documented with murine anti-H2-K b , -K d , and -L d mAbs by testing the expression on mutant cells of class I MHC molecules loaded with synthetic peptides or by performing selective immunoprecipitation of complexes containing different sets of peptide. In those studies, specific residues of the bound peptide essential for mAb recognition were identified, and the impact of exposed, but also buried, peptide residues on ␣1 and ␣2 MHC conformation was demonstrated (6)(7)(8)(9)(10)(11)(12). The same effect of peptides on mAb recognition of HLA class I molecules also has been observed by studying HLA-B27, -A11, or -B35/-B51 molecules loaded with various peptides and their analogues' ligands.…”

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confidence: 99%

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Influence of dominant HIV-1 epitopes on HLA-A3/peptide complex formation

Racapé

Connan

Hoebeke

et al. 2006

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

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The binding of peptides to MHC class I molecules induces MHC/ peptide complexes that have specific conformational features. Little is known about the molecular and structural bases required for an optimal MHC/peptide association able to induce a dominant T cell response. We sought to characterize the interaction between purified HLA-A3 molecules and four well known CD8 epitopes from HIV-1 proteins. To define the characteristics of HLA-peptide complex formation and to identify potential structural changes, we used biochemical assays that detect well formed complexes. We tested the amplitude, stability, and kinetic parameters of the interaction between HLA-A3, peptides, and anti-HLA mAbs. Our results show that the four epitopes Nef73-82, Pol325-333, Env37-46, and Gag20 -28 bind strongly to HLA-A3 molecules and form very stable complexes that are detected with differential patterns of mAb reactivity. The most striking result is the nonrecognition of the HLA-A3/Gag20 -28 complex by the A11.1M mAb specific to HLA-A3/-A11 alleles. To explain this observation, from the data published on HLA-A11 crystallographic structure, we propose molecular models of the HLA-A3 molecule complexed with Nef73-82, Pol325-333, and Gag20 -28 epitopes. In the HLA-A3/Gag20 -28 complex, we suggest that Arg at position P1 of the peptide may push the ␣2 helix residue Trp-167 of HLA-A3 and affect mAb recognition. Such observations may have great implications for T cell antigen receptor recognition and the immunogenicity of HLA/ peptide complexes. C rystallographic structure analysis of a series of class I MHC/peptide complexes revealed that peptides carrying specific MHC anchor residues bind in a large-solvent-exposed groove of the heavy chain. This binding groove consists of two long helices, ␣1 and ␣2, mounted on a floor of eight antiparallel ␤-strands. Polymorphic residues in the groove determine distinct binding pockets from A to F. Bound peptides adopt extended conformations that stretch from the N-to the C-terminal end of the groove, and their anchor residues, generally at positions P2 and P9/10, interact with pockets B and F, respectively (1-4). In most MHC complexes, peptides are partly buried in the binding site, and only a few side chains of the peptide pointing away from the groove toward the solvent are accessible for CD8 T cell recognition (1, 5).The impact of peptide binding on heavy-chain MHC conformation can be detected serologically by the observation of differential anti-MHC mAbs reactivities. This effect has been mainly documented with murine anti-H2-K b , -K d , and -L d mAbs by testing the expression on mutant cells of class I MHC molecules loaded with synthetic peptides or by performing selective immunoprecipitation of complexes containing different sets of peptide. In those studies, specific residues of the bound peptide essential for mAb recognition were identified, and the impact of exposed, but also buried, peptide residues on ␣1 and ␣2 MHC conformation was demonstrated (6-12). The same effect of peptides on mAb recogn...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Influence of dominant HIV-1 epitopes on HLA-A3/peptide complex formation

Racapé

Connan

Hoebeke

et al. 2006

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

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“…MHC class I molecules were found to acquire different conformations when different peptides were bound. Those changes were reflected by changes in the binding of anti-class I mAb (12)(13)(14)(15). Crystallization of MHC class I with different peptides enabled the detailed analysis of such changes (16,17).…”

Section: Discussionmentioning

confidence: 99%

“…It is well appreciated that peptides are able to change the conformation of MHC class I molecules. These changes were detected as gain͞loss of binding by anti-class I antibodies (12)(13)(14)(15) and by analysis of MHC class I molecules crystallized with single peptides (16,17). We sought to determine whether peptide-dependent changes occur in MHC class II that could be detected by mAbs.…”

Section: Introductionmentioning

confidence: 99%

Subtle conformational changes induced in major histocompatibility complex class II molecules by binding peptides

Chervonsky

Medzhitov

Denzin

et al. 1998

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

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ABSTRACT؉ or 25-9-17 ؊ conformation. Alloreactive T cells were also able to discriminate peptide-dependent variants of MHC class II molecules. Thus, peptides impose subtle structural transitions upon MHC class II molecules that affect T cell recognition and may thus be critical for T cell selection and autiommunity.It has been appreciated that major histocompatibility complex (MHC) class II molecules undergo conformational changes during their transport to the cell surface. These changes were detected as changes in mAb epitopes (1, 2, 3) or the ability to acquire stability in SDS (4). Another important factor in the structural transitions of MHC class II molecules appears to be the hydrogen ion concentration. A weakly acidic environment causes a loss of SDS stability and enhances the binding of 1-anilino-naphthalene-8-sulfonic acid, which is a marker for exposed hydrophobic sites (5, 6). Acidic pH enhances peptide binding (7-9) and is optimal for class II-associated invariant chain peptides (CLIP)͞peptide exchange catalyzed by HLA-DM molecules (10, 11), suggesting that protonation of certain residues in the MHC class II molecule may cause transient conformational shifts that allow optimal peptide binding and͞or exchange.Whether the mature MHC class II molecules expressed on the surface of antigen-presenting cells exist in different conformations relevant to T cell recognition remains unclear. It is well appreciated that peptides are able to change the conformation of MHC class I molecules. These changes were detected as gain͞loss of binding by anti-class I antibodies (12)(13)(14)(15) and by analysis of MHC class I molecules crystallized with single peptides (16,17). We sought to determine whether peptide-dependent changes occur in MHC class II that could be detected by mAbs. While analyzing anti-MHC class II mAb staining of cells expressing MHC class II complexes with single peptides, we found that mAb 25-9-17, which reacts with I-A b , fails to bind a complex between I-A b and E␣ peptide. This observation prompted us to seek explanations for this phenomenon. Indeed, we found that MHC class II molecules available for T cell recognition have subtle conformational differences dependent on the particular peptide they bind and that these alterations can also be detected by T cells. MATERIALS AND METHODS Mice. C57BL6͞J (B6), B10.A-H2 i5H2-Tla a (5R)͞SgSnEg (5R), and B6.C-H2 bm12 ͞KhEg (bm12) were obtained from The Jackson Laboratory. Invariant chain (Ii) knock-out animals were a gift from R.Flavell and I. Shachar (Yale University). Transgenic mice expressing covalently bound E␣ peptide (A b -pE␣)were a gift from P. Marrack (National Jewish Center, Denver, CO). H2-M-deficient mice were provided by Luc Van Kaer (Vanderbilt University, Nashville, TN).Cells and Tissue Culture. All cell cultures were performed in complete medium [Click's EHAA medium (Irvine Scientific) with 5% fetal calf serum (Intergen, Purchase, NY), 5 ϫ 10 Ϫ5 M 2-mercaptoethanol (Bio-Rad), 2 mM L-glutamine, 50 g͞ml gentamicin (GIBCO͞BRL)].The bm12-anti...

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“…Another study with K b -specific mAbs showed that by increasing the number of peptides, a larger number of K b -reactive mAbs appear to be peptide dependent. Peptide pools eluted from K b molecules that were immunoprecipitated with a peptide-selective mAb were successfully used to reconstitute empty K b molecules on T2-K b targets that were lysable by some allo-CTL clones (17). This suggests a relationship between alloreactive CTL and alloantibody recognition of MHC class I.…”

Section: Discussionmentioning

confidence: 99%

Impact of Peptides on the Recognition of HLA Class I Molecules by Human HLA Antibodies

Mulder

Eijsink

Kester³

et al. 2005

The Journal of Immunology

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MHC class I molecules expressed on cell surfaces are composed of H chain, β2-microglobulin and any of a vast array of peptides. The role of peptide in the recognition of HLA class I by serum HLA Abs is unknown. In this study, the solid-phase assay of a series (n = 11) of HLA-A2-reactive, pregnancy-induced, human mAbs on a panel (n = 12) of recombinant monomeric HLA-A2 molecules, each containing a single peptide, revealed peptide selectivity of the mAbs. The flow cytometry membrane staining intensities on the HLA-A2-transduced cell line K562, caused by these mAbs, correlated with the number of monomer species detected by the mAbs. Flow cytometry staining on HLA-A2-bearing cell lines of a variety of lineages was indicative of tissue selectivity of these HLA-A2 mAbs. This tissue selectivity suggests that the deleterious effect on allografts is confined to alloantibodies recognizing only HLA class I loaded with peptides that are derived from tissue-specific and household proteins. Since Abs that are only reactive with HLA loaded with irrelevant peptides are expected to be harmless toward allografts, the practice of HLA Ab determination on lymphocyte-derived HLA deserves reconsideration.

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Alloantibodies can discriminate class I major histocompatibility complex molecules associated with various endogenous peptides.

Cited by 38 publications

References 26 publications

Influence of dominant HIV-1 epitopes on HLA-A3/peptide complex formation

Influence of dominant HIV-1 epitopes on HLA-A3/peptide complex formation

Subtle conformational changes induced in major histocompatibility complex class II molecules by binding peptides

Impact of Peptides on the Recognition of HLA Class I Molecules by Human HLA Antibodies

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