Effect of mutations and variations of HLA-A2 on recognition of a virus peptide epitope by cytotoxic T lymphocytes.

McMichael, Andrew J.; Gotch, Frances; Santos-Aguado, J; Strominger, Jack L.

doi:10.1073/pnas.85.23.9194

Cited by 98 publications

(66 citation statements)

References 27 publications

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“…Class I HLA molecules are involved in T cell-mediated cytotoxicity against virally infected cells as restriction molecules and it has been shown that not all class I antigens are recognized equally by cytotoxic T lymphocytes specific for different virus antigens [23,24]. These observations, explained by the molecular structure of class I HLA antigens [25] suggest that our findings are due to a different ability for antigen presentation by B51 + and B52+ lymphocytes.…”

Section: Discussioncontrasting

confidence: 38%

HLA-associated susceptibility to HIV-1 infection

Gavarini¹,

Scorza²,

Lazzarin³

et al. 1992

Clinical and Experimental Immunology

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SUMMARYWe studied HLA antigen distribution of 50 heterosexual partners of HIV+ drug abusers with more than I year of sexual exposure to HIV, 36 children born to seropositive mothers and 61 haemophiliac patients exposed to presumably infectious clotting factor concentrates. B52 and B44 antigens were associated with HIV resistance while B51 was associated with HIV susceptibility. Forty-nine HIV+ drug abusers, spouses of heterosexual partners studied and 25 HIV+ mothers of the children were also typed. DRl 1 phenotype was associated with infectiousness of HIV+ subjects. Our data suggest that the HLA region controls susceptibility to infection with HIV and infectiousness of HIV+ subjects in different risk groups.

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Section: Discussioncontrasting

confidence: 38%

HLA-associated susceptibility to HIV-1 infection

Gavarini¹,

Scorza²,

Lazzarin³

et al. 1992

Clinical and Experimental Immunology

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“…These two mutations had no effect on allorecognition; nor did they affect recognition of two distinct influenza virus peptides by appropriate clones (24,25). (ii) Residues on the sides ofthe helices facing into the site (residues 63, 66, 70, 74, 77, 80, 152, and 156).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, changes in the two residues examined that are outside of the groove, residues 43 and 107, did not affect recognition, whereas each of the other mutations had an effect on at least one CTL clone. These mutations include residue 9 (which points upward into the site from a P3 strand on the floor) and residue 70 (which points inward from the a1-helix and interacts with residue 9), as well as residue 74, which had no effect in one virus peptide-specific MHC-restricted CTL recognition study (24) but drastically affected another (25). (iv) The most profound effect was found with mutations at both residues 62 and 63; all CTL examined failed to recognize this mutant.…”

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confidence: 99%

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Alloreactivity studied with mutants of HLA-A2.

Santos-Aguado

Crimmins

Mentzer

et al. 1989

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

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Based on the crystal structure of HLA-A2.1 and the recognition of a panel of mutant HLA-A2.1 molecules by a large number of alloreactive cytotoxic T lymphocyte clones, a model to explain alloreactivity is described. In this model recognition of an allogeneic major histocompatibility complex molecule by a self-restricted T-cell receptor occurs as the result ofaccommodation by the receptor ofa few amino acid differences in the major histocompatibility complex moleculei.e., cross-recognition. Alloreactivity is the result of the presence in the foreign antigen binding site of the allogeneic major histocompatibility complex molecule of unusual self-peptides, reactivity to which could not have been eliminated by negative thymic selection.Class I major histocompatibility complex (MHC) molecules (HLA molecules in man) were originally identified as the target structures responsible for the humoral (alloantibody) and cellular (alloreactive cytotoxic T lymphocyte) responses generated during the rejection of transplanted foreign tissue (1). However, the central role of these highly polymorphic cellsurface glycoproteins is to serve as restricting elements in the recognition by T cells of virus-infected, chemically modified, or neoplastic cells (2-5). The regions in contact between the molecules involved in the recognition process (T-cell receptor, class I MHC molecule, peptide, and accessory molecules) are not yet precisely described, and the nature and and biophysical characteristics of these interactions (6) remain to be determined. Identification of specific residues on class I MHC molecules involved in the recognition by human cytotoxic T lymphocytes (CTL) has been facilitated over the last few years by the structural characterization of natural HLA variants initially distinguished by cytotoxicity assays (7) and/or isoelectric focusing (8). In population studies, sequence comparison of these otherwise serologically similar HLA molecules (9), exon shuffling (10,11), and site-directed mutagenesis (12)(13)(14)(15) have all highlighted the importance of polymorphic residues in the a1 and/or a2 domains of the HLA molecule in the recognition process. Moreover, the class I MHC molecules were shown to present peptides derived from processed antigens to the receptor of cytotoxic T cells (16, 17). Elucidation ofthe crystal structure ofHLA-A2 revealed a platform ofeight antiparallel (3 strands topped by two a-helices (18,19). A prominent groove between the helices was identified as the site for binding of foreign peptides.In the present study, site-directed mutagenesis of HLA-A2

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“…Each mutation results in a unique pattern of stimulation of the T-cell clones, and each DR3-restricted T cell clone is stimulated by a different subset of the mutants. This complex relationship of fine structure to antigen-presenting function has been a consistent finding among the murine and human MHC class I and class II molecules examined to date (8,(30)(31)(32)(33)(34)(35)(36)(37) (Table 2). A direct role in antigen presentation for position 74 is consistent with the predicted functional importance of polymorphic residues.…”

Section: Discussionmentioning

confidence: 89%

Point mutations define positions in HLA-DR3 molecules that affect antigen presentation.

Mellins

Arp

Singh

et al. 1990

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

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Allelic differences in major histocompatibility complex (MHC)-encoded class II molecules affect both the binding of immunogenic peptides to class II molecules and the recognition ofMHC molecule-peptide complexes by T cells. As yet, there has been no extensive mapping of these functions to the rme structure of human class II molecules. To determine sites on the HLA-DR3 molecule involved in antigen presentation to T cells, we used monoclonal antibodies specific for HLA-DR3 to immunoselect mutants of a B-lymphoblastoid line. We located the sites of single amino acid substitutions in the HLA-DR3 molecule and correlated these structural changes with patterns of recognition by HLA-DR3-restricted, antigenspecific T cells, allospecific T cells, and allospecific anti-DR3 monoclonal antibodies. We analyzed seven mutations. One mutation, at position 74 in domain 1 of the DR j3 chain, affected recognition by all T cells tested, whereas others, at positions 9, 45, 73, 151, and 204 of the DR P chain and position 115 of the DR a chain, altered recognition by some T cells, but not others. Each of the substitutions resulted in a unique pattern of T-cell stimulation. In addition, each T-cell clone recognized a different subset of the mutants. These results indicate that different residues of the DR3 molecule are involved in presentation of antigen to different DR3-restricted T cells. These studies further show that substitutions which most likely affect peptide binding alter recognition of DR3 molecules by an alloreactive T-cell clone and some allospeciflic antibodies.Major histocompatibility complex (MHC) molecules are highly polymorphic cell surface glycoproteins whose most evident and best understood function is to present immunogenic peptide antigens to T lymphocytes (1, 2). In addition, allelic variation in MHC class II molecules is associated with susceptibility or resistance to autoimmune diseases (3). The essential relationship between the polymorphism of MHC molecules and their function is well documented (4) and suggests that the locations of the hypervariable regions of MHC class II molecules are likely to identify functional domains (5, 6). However, only a few studies have examined the particular contribution of individual class II residues to antigen presentation, in murine (7-9) or human (10) systems.Brown et al. (11) have proposed a structural model of the class II binding domain for antigen, based on the crystal structure of an MHC class I molecule. This model identifies amino acid residues that are involved in peptide binding or in T-cell interactions based on their locations and the orientation of their side chains. One experimental approach for determining the function of individual amino acid residues, and thus testing the model's predictions, is to generate somatic cell mutants with single amino acid substitutions in class II molecules, to map their mutations, and to characterize their functional defects. Using a B-lymphoblastoid cell line (B-LCL) as progenitor, we have immunoselected mutants with sin...

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Effect of mutations and variations of HLA-A2 on recognition of a virus peptide epitope by cytotoxic T lymphocytes.

Cited by 98 publications

References 27 publications

HLA-associated susceptibility to HIV-1 infection

HLA-associated susceptibility to HIV-1 infection

Alloreactivity studied with mutants of HLA-A2.

Point mutations define positions in HLA-DR3 molecules that affect antigen presentation.

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