HLA restriction of human cytotoxic T lymphocytes specific for influenza virus. Poor recognition of virus associated with HLA A2.

McMichael, A

doi:10.1084/jem.148.6.1458

Cited by 84 publications

(45 citation statements)

References 13 publications

(7 reference statements)

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“…The loss of Class I antigen expression has implications for the associative recognition of putatively antigenic tumour cells by cytotoxic T lymphocytes (McMichael, 1978). The Class Inegative populations could conceivably have arisen through immunoselection of Class I-positive clones expressing tumour-associated antigens.…”

Section: Discussionmentioning

confidence: 99%

Distribution of histocompatibility and leucocyte differentiation antigens in normal human colon and in benign and malignant colonic neoplasms

Csiba¹,

Whitwell²,

Moore³

1984

Br J Cancer

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Summary Monoclonal antibodies (McAbs) directed against the framework determinants of Class I and Class II products of the major histocompatibility complex (MHC) and against leucocyte differentiation antigens were used in an indirect immunoperoxidase technique to study their expression in normal, benign (adenomatous polyps) and malignant disease of the colon. Class I products (detected by the McAb 2AI) were strongly expressed on all cell types in normal and benign tissues but some carcinomas exhibited a heterogenous pattern of epithelial cell staining and 4/15 were completely negative. Class II products (detected by TDR3 1.1) were strongly expressed on cells (mainly B lymphocytes) within the lamina propria. In carcinomas TDR31.1 staining was mainly interstitial, but in 2/15, DR+ epithelial cells were also detected. In normal and benign tissues, leucocytes (reactive with 2D1) found predominantly in the lamina propria, comprised T cells mainly of the helper/inducer (OKT4) subset, DR+ cells in approx. equivalent proportion and a few OKM1+ cells mostly of macrophage morphology. Occasional intraepithelial lymphocytes were of cytotoxic/suppressor (OKT8) phenotype. In malignant neoplasms, there was wide inter and intra-tumour variation in the proportion of leucocytes which were heterogeneous with respect to cell type and confined mainly to the stroma. T cells were consistently predominant, but B cells and macrophages were also present. Two neoplasms showed unequivocal evidence of a shift (relative to peripheral blood) in favour of the OKT8+ subset, but in the majority of tumours OKT4+; and OKT8+ cells were present in roughly similar proportions. Natural killer cells (monitored with Leu7, HNK1) were virtually undetectable in both normal and malignant tissues. There were no apparent correlations between the extent and type of leucocyte infiltration, tumour differentiation or expression of MHC products. Some implications for the extrapolation of in vitro data on leucocyte function to the in vivo situation are discussed.

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Section: Discussionmentioning

confidence: 99%

Distribution of histocompatibility and leucocyte differentiation antigens in normal human colon and in benign and malignant colonic neoplasms

Csiba¹,

Whitwell²,

Moore³

1984

Br J Cancer

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“…When HLA restriction ofinfluenza virus-specific CTL was first studied in detail, it was found that virus-infected cells were sometimes not recognized by CTL that appeared to share HLA-A2 (18,19). This was shown to be due to the existence of variant HLA-A2 molecules (14,19), which differed in three or four amino acids from the common HLA-A2 molecule (17,(19)(20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

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

McMichael

Gotch

Santos-Aguado

et al. 1988

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

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Cytotoxic T lymphocytes (CTL) specific for influenza A virus were prepared from 15 donors. Those with HLA-A2 recognized autologous or HLA-A2-matched Blymphoblastoid cells in the presence of synthetic peptide representing residues 55-73 or 56-68 of the virus matrix protein sequence. Influenza A virus-specific CTL from donors without HLA-A2 or with an HLA-A2 variant type failed to respond to this peptide. CTL lines specific for HLA-A2 plus peptide did not lyse peptide-treated target cells from HLA-A2 variant donors. They also failed to lyse peptide-treated cells with point mutations that had been inserted into HLA-A2 at positions 62-63, 66, 152, and 156 and, in some instances, mutations at positions 9 and 70. CTL lysed peptide-treated target cells with mutations in HLA-A2 at positions 43, 74, and 107. The results imply that this defined peptide epitope therefore interacts with HLA-A2 in the binding groove so that the long a-helices of HLA-A2 make important contact with the peptide at positions 66, 152, and 156. Different amino acids at position 9, which is in the floor of the peptide binding groove of HLA-A2 and the closely related position 70, modulate the peptide interaction so that some T-cell clones react and some do not.Influenza virus-specific cytotoxic T lymphocytes (CTL) recognize both external and internal proteins of virus on infected cells (1-4). A major component of this response is directed toward the nucleoprotein in mice (2, 3) and nucleoprotein and the matrix protein in humans (4). Class I molecules of the major histocompatibility complex (MHC) were shown to play a major role in this process, first by the demonstration of MHC restriction, where CTL recognize only histocompatible infected target cells (5), and more recently by the finding that MHC type determines, directly or indirectly, the epitope recognized by CTL (6-8). The mechanism underlying these effects became clearer when it was found that influenza virus-specific CTL reacted with short synthetic peptides based on virus protein sequences when presented by uninfected target cells of the appropriate MHC type (9). This implied that virus proteins were processed to peptide fragments that bound to MHC molecules prior to recognition by CTL. The crystal structure of HLA-A2 revealed unidentified electron density, probably peptide, present in a pocket on the surface of the molecule (10). This groove was formed by two a-helices lying across an eightstranded P-sheet. Nearly all of the polymorphic amino acid residues in the class I molecule were located around this groove (11). Thus, it is likely that the peptide 55-73 from influenza virus matrix protein, which has been shown to be recognized by CTL in association with HLA-A2 (8), binds in this groove.The experiments described here test the effects of natural and deliberately introduced mutations in HLA-A2 on recognition of the matrix peptide by CTL. It is shown that mutations in HLA-A2 located around the groove impaired recognition but that there were variable effects with different CTL clone...

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“…Thus it is likely that both normal and malignant breast epithelial cells exhibit a bias toward low expression of HLA. Since at least cytotoxic T cells recognise target antigens in association with HLA-A, B, C antigens (McMichael, 1978) (Rowe et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

Characterisation of breast cancer infiltrates using monoclonal antibodies to human leucocyte antigens

Rowe¹,

Beverley²

1984

Br J Cancer

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Summary Serial frozen sections from eleven patients with malignant breast tumours and five patients with benign disease were studied by indirect immunoperoxidase using a panel of mouse monoclonal antibodies to human leucocyte antigens. More infiltrating leucocytes were seen in tumour sections than those of benign conditions. A considerable proportion of the infiltrating cells were T cells, and more of these were of the suppressor/cytotoxic subset than the helper/inducer subset. The T cells were apparently not all activated as indicated by lower levels of staining with anti HLA-DR than anti-leucocyte antibody. Diffuse staining was sometimes seen with HLA-DR and T cell subset antibodies. Tumour cells did not stain or were only very weakly positive with anti HLA-A, B, C.

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HLA restriction of human cytotoxic T lymphocytes specific for influenza virus. Poor recognition of virus associated with HLA A2.

Cited by 84 publications

References 13 publications

Distribution of histocompatibility and leucocyte differentiation antigens in normal human colon and in benign and malignant colonic neoplasms

Distribution of histocompatibility and leucocyte differentiation antigens in normal human colon and in benign and malignant colonic neoplasms

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

Characterisation of breast cancer infiltrates using monoclonal antibodies to human leucocyte antigens

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