Restored expression of major histocompatibility class I molecules by gene transfer of a putative peptide transporter

CYTOTOXIC T lymphocytes recognize antigen-derived peptides bound to major histocompatibility complex (MHC) class I molecules with which they assemble in the endoplasmic reticulum or in an undefined subcompartment1–10. There is genetic evidence that the peptides that are products of cytosolic protein degradation are transported into this compartment by a peptide supply factor (PSF), encoded in the MHC class II region11. Like the corresponding genes RING4, HAM1 and mtpl (refs 12–14), PSF is related to the multidrug-resistance family of transporters11 and may be a peptide pump, as translocation of peptides across membranes must occur independently of the secretory pathway15. There is, however, no functional evidence for this role so far. Here we report gene transfer experiments showing that expression of PSF complementary DNA in the human lymphoblastoid cell line mutant 721.134 (refs 11,16,17) restores normal levels of surface HLA-A2 and -B5. No similar effect was observed in 721.174 mutant cells, in which a homozygous deletion includes PSF among several other closely linked genes11. At least one of these genes may therefore also be required for PSF function.

[1]  S. Nathenson,et al.  Isolation of an endogenously processed immunodominant viral peptide from the class I H–2Kb molecule , 1990, Nature.

[2]  H. Orr,et al.  Mutations that impair a posttranscriptional step in expression of HLA-A and -B antigens. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[3]  R. Mulligan,et al.  Selection for animal cells that express the Escherichia coli gene coding for xanthine-guanine phosphoribosyltransferase. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[4]  H. Orr,et al.  Transfer of cloned human class I major histocompatibility complex genes into HLA mutant human lymphoblastoid cells , 1986, Molecular and cellular biology.

[5]  J. Davey,et al.  Cytotoxic T cells recognize fragments of the influenza nucleoprotein , 1985, Cell.

[6]  Hidde L. Ploegh,et al.  Direct binding of peptide to empty MHC class I molecules on intact cells and in vitro , 1990, Cell.

[7]  M. Bevan,et al.  Introduction of soluble protein into the class I pathway of antigen processing and presentation , 1988, Cell.

[8]  T. Elliott,et al.  Assembly of MHC class I molecules analyzed in vitro , 1990, Cell.

[9]  S. Beck,et al.  Sequences encoded in the class II region of the MHC related to the 'ABC' superfamily of transporters , 1990, Nature.

[10]  P. Cresswell,et al.  Presentation of viral antigen controlled by a gene in the major histocompatibility complex , 1990, Nature.

[11]  J. Monaco,et al.  MHC class II region encoding proteins related to the muKidrug resistance family of transmembrane transporters , 1990, Nature.

[12]  C. Barnstable,et al.  Monoclonal Antibodies for Analysis of the HLA System , 1979, Immunological reviews.

[13]  J. Monaco,et al.  Transport protein genes in the murine MHC: possible implications for antigen processing. , 1990, Science.

[14]  B. Haynes,et al.  Cell lines producing human T-cell lymphoma virus show altered HLA expression , 1983, Nature.

[15]  K. Gould,et al.  Cytotoxic T lymphocytes recognize influenza haemagglutinin that lacks a signal sequence , 1986, Nature.

[16]  J. Strominger,et al.  A new cluster of genes within the human major histocompatibility complex. , 1989, Science.

[17]  P. Cresswell,et al.  Impaired assembly and transport of HLA‐A and ‐B antigens in a mutant TxB cell hybrid. , 1986, The EMBO journal.

[18]  P. Parham,et al.  Amino acid residues 56 to 69 of HLA-A2 specify an antigenic determinant shared by HLA-A2 and HLA-B17. , 1986, Journal of immunology.

[19]  H. Ljunggren,et al.  Association of class I major histocompatibility heavy and light chains induced by viral peptides , 1989, Nature.

[20]  R. Demars,et al.  Homozygous deletions that simultaneously eliminate expressions of class I and class II antigens of EBV-transformed B-lymphoblastoid cells. I. Reduced proliferative responses of autologous and allogeneic T cells to mutant cells that have decreased expression of class II antigens. , 1984, Human immunology.

[21]  T. Braciale,et al.  Differences in antigen presentation to MHC class I-and class II- restricted influenza virus-specific cytolytic T lymphocyte clones , 1986, The Journal of experimental medicine.

[22]  B. Haynes,et al.  Description of monoclonal antibody defining an HLA allotypic determinant that includes specificities within the B5 cross-reacting group. , 1982, Human immunology.

[23]  R. Demars,et al.  A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway , 1990, Nature.

[24]  M. A. Saper,et al.  The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens , 1987, Nature.