The Role of Amino Acid Position and Side Chain Structure in Serological and CTL-Defined Epitopes on the HLA-A2.1 Molecule

Hogan, Kevin T.; Clayberger, Carol; Shimojo, Naoki; Biddison, William E.; Krensky, Alan M.; Engelhard, Víctor H.

doi:10.1007/978-3-642-75442-5_12

Transgenic Mice and Mutants in MHC Research 1990

DOI: 10.1007/978-3-642-75442-5_12

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The Role of Amino Acid Position and Side Chain Structure in Serological and CTL-Defined Epitopes on the HLA-A2.1 Molecule

Kevin T. Hogan

Carol Clayberger

Naoki Shimojo

et al.

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1994

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“…Induction of peptide-specific CTLs in vitro was performed with unseparated PBLs exactly as described for the induction of influenza virus matrix protein peptide 58-66 CTLs (27). Purified CD8+ responder cells were isolated from PBLs with magnetic beads coupled with anti-CD8 antibody (Dynabeads M-450 CD8; Dynal, Lake Success, NY) and detached using a polyclonal anti-immunoglobulin antibody (DetachaBead; Dynal) as described by the manufacturer.…”

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“…T-cell clones were isolated from limiting dilution cultures with responder cells at 10 and 1 cell per well with 20 units of recombinant interleukin 2 per ml. Cytolytic activity was assayed by Na251CrO4 release as described (27) using Hmy2.ClR cells (28) (a gift of Peter Cresswell, Yale University) that were transfected with HLA-A2 (A2-Hmy), HLA-A1 (A1-Hmy), and HLA-B44 (B44-Hmy). A hybrid clone (MO3.13) from a fusion of the rhabdomysarcoma RD.TG6 and mixed human glial cells (29) was a gift of Neil Cashman (McGill Univ., Montreal).…”

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“…A hybrid clone (MO3.13) from a fusion of the rhabdomysarcoma RD.TG6 and mixed human glial cells (29) was a gift of Neil Cashman (McGill Univ., Montreal). MO3.13 was transfected with HLA-A2 cDNA in the RSV.Neo vector as described (27). Cell surface expression of HLA-A2 was assessed by indirect immunofluorescence with the anti-HLA-A2 antibody BB7.2 as described (27).…”

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“…MO3.13 was transfected with HLA-A2 cDNA in the RSV.Neo vector as described (27). Cell surface expression of HLA-A2 was assessed by indirect immunofluorescence with the anti-HLA-A2 antibody BB7.2 as described (27). HLA-A2-transfected and untransfected MO3.13 cells were used as targets after stimulation with 100 nM phorbol 12-myristate 13-acetate (PMA; Sigma) and 200 units of IFN-y per ml (Genzyme) for 3 days to induce expression of myelin and MHC genes (29).…”

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confidence: 99%

“…HLA-A2-transfected and untransfected MO3.13 cells were used as targets after stimulation with 100 nM phorbol 12-myristate 13-acetate (PMA; Sigma) and 200 units of IFN-y per ml (Genzyme) for 3 days to induce expression of myelin and MHC genes (29). Results ofcytotoxicity assays are expressed as mean % specific lysis of triplicate determinations (27).…”

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confidence: 99%

See 4 more Smart Citations

Autoreactive CD8+ T-cell responses to human myelin protein-derived peptides.

Tsuchida

Parker

Turner

et al. 1994

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

146

102

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Identification of the targets of autoreactive T cells is important for understanding the pathogenesis of many autoimmune diseases. In multiple sclerosis, myelin proteins are thought to be the targets of autoreactive T-cell responses. To date only major histocompatibility complex class 11-restricted CD4+ T-cell responses to myelin proteins have been investigated. In the present study, the ability of self peptides derived from human myelin proteins to induce autoreactive CD8+ T-cell responses has been assessed. Peptide sequences from human myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), and myelin oligodendrocyte glycoprotein have been identified that bind to and form stable complexes with HLA-A2. MBP 110-118, PLP 80-88, MAG 287-295, MAG 509-517, and MAG 556-564 were all able to induce peptide-specific HLA-A2-restricted CD8+ cytotoxic T-lymphocyte (CTL) responses in vitro in HLA-A2+ individuals. CTLs specific for MBP 110-118 and MAG 556-564 could recognize endogenously processed antigens presented by HLA-A2. CTL clones reactive to MBP 110-118 and MAG 556-564 produced tumor necrosis factor a and a subset ofthese clones also produced interferon y. These results demonstrate that (i) self peptides derived from human myelin proteins can induce autoreactive CD8+ CTLs and (ii) these CD8+ T cells produce cytokines thought to be important in mediating demyelinating disease. These studies provide an experimental approach for the assessment of CD8+ T-cell responses in such autoimmune diseases.sively by MHC class I molecules (17, 18), and adult oligodendrocytes constitutively express MHC class I molecules but do not express class II MHC molecules, even when stimulated by interferon y (IFN-y) (19). Thus, if adult oligodendrocytes are targets for T-cell reactivity, they will most likely be recognized by MHC class I-restricted CD8+ T cells but not by class II-restricted CD41 T cells. (iii) In an animal model of demyelinating disease, experimental allergic encephalomyelitis (EAE), CD8+ T cells have been shown to have an immunoregulatory effect on the course of the disease (20, 21). Despite these implications that autoreactive CD8+ T-cell responses may play an important role in MS, a successful experimental approach to this question has not yet been reported.To investigate the possible role(s) of CD8+ T-cell responses to myelin proteins in the pathogenesis of demyelinating disorders, we have taken advantage of recent advances in the ability to predict peptide epitopes presented by the HLA class I molecule, . A computer-based algorithm has been devised that predicts the stability of HLA-A2-peptide complexes by quantitating positive and negative effects on binding by each amino acid within a nonamer peptide (22). This algorithm has been used to predict HLA-A2 binding nonamer peptides from the myelin proteins MBP, PLP, MAG, and MOG. In this report we have identified HLA-A2-restricted epitopes derived from these proteins that are capable of inducing CD8+ cytotoxic T-lymphocyte (CTL)...

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

See 3 more Smart Citations

Autoreactive CD8+ T-cell responses to human myelin protein-derived peptides.

Tsuchida

Parker

Turner

et al. 1994

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

146

102

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The Role of Amino Acid Position and Side Chain Structure in Serological and CTL-Defined Epitopes on the HLA-A2.1 Molecule

Cited by 1 publication

References 24 publications

Autoreactive CD8+ T-cell responses to human myelin protein-derived peptides.

Autoreactive CD8+ T-cell responses to human myelin protein-derived peptides.

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