Summary
Recent investigations have shown that malignant transformation may down-regulate the expression of class I HLA molecules, β2-microglobulin (β2m) and members of the antigen-processing machinery. In the present study, we HLA-genotyped and identified at a biochemical level the three (HLA-A25, -B8, -Cw7) class I alleles expressed by the previously described [D’Urso CM et al (1992) J Clin Invest : 284–292] β2m-defective human melanoma FO-1 cell line and tested their ability to interact with calnexin, calreticulin and the TAP (transporter associated with antigen processing) complex. All these alleles were found to bind calnexin, but not calreticulin or the poorly expressed TAP complex, both in parental and β2m-transfected FO-1 cells, demonstrating a complex defect of class I expression in FO-1 cells. In these conditions, Cw7 heavy chains interacted with calnexin more strongly than A25 and B8, and preferentially accumulated in the endoplasmic reticulum, in both a calnexin-associated and a calnexin-free form. In addition, they could be transported to the cell surface at low levels even in the absence of β2m, without undergoing terminal glycosylation. These results establish a parallel between HLA-C and the murine Db and Ld molecules which have been found to be surface expressed and functional in β2m-defective cells. They also demonstrate distinctive features of HLA-C molecules. We propose that the accumulation of several assembly intermediates of HLA-C might favour the binding of peptide antigens not readily bound by HLA-A and -B molecules in neoplastic cells with suboptimal class I expression.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Allen, H., Fraser, J., Flyer, D., Calvin, S. & Flavell, R. (1986). β2-microglobulin is not required for cell surface expression of the murine class I histocompatibility antigen H-2Db or of a truncated H-2Db. Proc Natl Acad Sci USA 83: 7447–7451.
Bicknell, D. C., Rowan, A. & Bodmer, W. F. (1994). β2-microglobulin mutations: a study of established colorectal cell lines and fresh tumors. Proc Natl Acad Sci USA 91: 4751–4755.
Cook, R. J., Solheim, J. C., Connolly, J. M. & Hansen, T. H. (1995). Induction of peptide-specific CD8+ CTL clones in β2-microglobulin deficient mice. J Immunol 154: 47–57.
D’Urso, C. M., Wang, Z., Cao, Y., Tatake, R., Zeff, R. A. & Ferrone, S. (1992). Lack of HLA class I antigen expression by cultured melanoma cell FO-1 due to a defect in β2m gene expression. J Clin Invest 87: 284–292.
Degen, E. & Williams, D. (1991). Participation of a novel 88-kD protein in the biogenesis of murine class I histocompatibility molecules. J Cell Biol 112: 1099–1115.
Elliott, T. (1991). How do peptides associate with MHC class I molecules?. Immunol Today 12: 386–388.
Elliott, T. (1997). How does TAP associate with MHC class I molecules?. Immunol Today 18: 375–379.
Fellous, M., Kamoun, M., Wiels, J., Dausset, J., Clements, G., Zeuthen, J. & Klein, G. (1977). Induction of HLA expression in Daudi cells after cell fusion. Immunogenetics 5: 423–436.
Garrido, F., Cabrera, T., Concha, A., Glew, S., Ruiz-Cabello, F. & Stern, P. L. (1993). Natural history of HLA expression during tumour development. Immunol Today 14: 491–499.
Gattoni-Celli, S., Kirsch, K., Timpane, R. & Isselbacher, K. J. (1992). β2-microglobulin gene is mutated in a human colon cancer cell line (HCT) deficient in the expression of HLA class I antigens on the cell surface. Cancer Res 52: 1201–1204.
Giacomini, P., Beretta, A., Nicotra, M. R., Ciccarelli, G., Martayan, A., Cerboni, C., Lopalco, L., Bini, D., Delfino, L., Ferrara, G. B., Siccardi, A. G. & Natali, P. G. (1997). HLA-C heavy chains free of β2m: distribution in normal tissues and neoplastic lesions of non-lymphoid origin and IFN-γ responsiveness. Tissue Antigens 50: 555–566.
Hajek-Rosenmayr, A., Jungl, L., Stammler, M. & Kirnbauer, M. (1989). HLA-C locus antigens seen by one-dimensional isoelectric focusing: definition of the so far known HLA-C specificities and of two subtypes. Hum Immunol 26: 227–236.
Hansen, T. H. & Lee, D. R. (1997). Mechanism of class I assembly with β2 microglobulin and loading with peptide. Adv Immunol 64: 105–137.
Hansen, T. H., Myers, N. B. & Lee, D. R. (1988). Studies of two antigenic forms of Ld with disparate β2-microglobulin associations suggest that β2m facilitates the folding of the α1 and α2 domains during de novo synthesis. J Immunol 140: 3522–3527.
Lehmann-Grube, F., Dralle, H., Utermohlen, O. & Lohler, J. (1994). MHC class I molecule-restricted presentation of viral antigen in β2-microglobulin-deficient mice. J Immunol 153: 595–603.
Long, E. O. & Wagtmann, N. (1997). Natural killer cell receptors. Curr Opin Immunol 9: 344–350.
Machold, R. P., Andrée, S., Van Kaer, L., Ljunggren, H-G & Ploegh, H. L. (1995). Peptide influences the folding and intracellular transport of free major histocompatibility complex class I heavy chains. J Exp Med 181: 1111–1122.
Markwell, M. A. & Fox, C. F. (1978). Surface specific iodination of membrane proteins of viruses and eukaryotic cells using 1,2,3,4 tetrachloro-3α, 6β-diphenylglycoluril. Biochemistry 17: 4807–4817.
Martayan, A., Fiscella, M., Setini, A., Ciccarelli, G., Gambari, R., Feriotto, G., Beretta, A., Siccardi, A. G., Appella, E. & Giacomini, P. (1997). Conformation and surface expression of free HLA-CW1 heavy chains in the absence of β2-microglobulin. Hum Immunol 53: 23–33.
Neefjes, J. J. & Ploegh, H. L. (1988). Allele and locus-specific differences in cell surface expression and the association of HLA class I heavy chain with β2-microglobulin: differential effects of inhibition of glycosylation on class I subunit association. Eur J Immunol 18: 801–810.
Neefjes, J. J., Breur-Vriesendorp, B. S., Seventer, I., Ivanyi, P. & Ploegh, H. L. (1986). Improved biochemical method for the analysis of HLA-class I antigens. Definition of new HLA-class I subtypes. Immunology 16: 169–181.
Neisig, A., Melief, C. J. M. & Neefjes, J. J. (1998). Reduced cell surface expression of HLA-C molecules correlates with restricted peptide binding and stable TAP interaction. J Immunol 160: 171–179.
Ortmann, B., Copeman, J., Lehner, P. J., Sadasivan, B., Herberg, J. A., Grandea, A. G., Riddell, S. R., Tampé, R., Spies, T., Trowsdale, J. & Cresswell, P. (1997). A critical role for tapasin in the assembly and function of multimeric MHC class I-TAP complexes. Science 277: 1306–1309.
Parham, P., Barnstable, C. J. & Bodmer, W. F. (1979). Use of monoclonal antibody (W6/32) in structural studies of HLA-A,B,C antigens. J Immunol 23: 342–349.
Pellegrino, M. A., Ng, A. K., Russo, C. & Ferrone, S. (1982). Heterogenous distribution of determinants defined by monoclonal antibodies on HLA-A, -B antigen bearing molecules. Transplantation 34: 18–23.
Pera, C., Delfino, L., Morabito, A., Longo, A., Johnston-Dow, L., White, C. B., Colonna, M. & Ferrara, G. B. (1997). HLA-A typing: comparison between serology, the amplification refractory mutation system with polymerase chain reaction and sequencing. Tissue Antigens 50: 372–379.
Porgador, A., Mandelboim, O., Restifo, N. P. & Strominger, J. L. (1997). Natural killer cell lines kill autologous β2m-deficient melanoma cells: implications for cancer immunotherapy. Proc Natl Acad Sci 94: 13140–13145.
Potter, T. A., Boyer, C., Schmitt-Verhulst, A. M., Goldestein, P. & Rajan, T. V. (1984). Expression of H-2D on the cell surface in the absence of detectable β2-microglobulin. J Exp Med 84: 317–325.
Prasad, V. K. & Yang, S. Y. (1996). Allele assignment for HLA-A, -B, and -C genes to the Tenth International Histocompatibility Workshop cell lines. Tissue Antigens 47: 538–546.
Rajagopalan, S. & Brenner, M. B. (1994). Calnexin retains unassembled major histocompatibility complex class I free heavy chains in the endoplasmic reticulum. J. Exp. Med 180: 407–412.
Sadasivan, B., Lehner, P. J., Ortmann, B., Spies, T. & Cresswell, P. (1996). Roles for calreticulin and a novel glycoprotein, tapasin, in the interaction of MHC class I molecules with TAP. Immunity 5: 103–114.
Salter, R. D. & Cresswell, P. (1986). Impaired assembly and transport of HLA-A and -B antigens in a mutant TxB cell hybrid. EMBO J 5: 943–949.
Seliger, B., Maeurer, M. J. & Ferrone, S. (1997). TAP off – tumors on. Immunol Today 18: 292–299.
Setini, A., Beretta, A., De Santis, C., Meneveri, R., Martayan, A., Mazzilli, M. C., Appella, E., Siccardi, A. G., Natali, P. G. & Giacomini, P. (1996). Distinctive features of the α1 domain α helix of HLA-C heavy chains free of β2-microglobulin. Hum Immunol 46: 69–81.
Shimizu, Y. & Demars, R. (1989). Production of human cells expressing individual transferred HLA-A,-B,-C genes using an HLA-A, -B,-C null human cell line. J Immunol 142: 3320–3328.
Smith, J. D., Myers, N. B., Gorka, J. & Hansen, T. H. (1993). Model for the in vivo assembly of nascent Ld class I molecules and for the expression of unfolded Ld molecules at the cell surface. J Exp Med 178: 2035–2046.
Solheim, J. C., Carreno, B. M. & Hansen, T. H. (1997a). Are transporter associated with antigen processing (TAP) and Tapasin class I MHC chaperones? J Immunol 158: 541–543.
Solheim, J. C., Harris, M. R., Kindle, C. S. & Hansen, T. H. (1997b). Prominence of β2-microglobulin, class I heavy chain conformation, and tapasin in the interactions of class I heavy chain with calreticulin and the transporter associated with antigen processing. J Immunol 158: 2236–2241.
Stam, N. J., Spits, H. & Plogh, H. L. (1986). Monoclonal antibodies raised against denatured HLA-B locus heavy chains permit biochemical characterization of certain HLA-C products. J Immunol 137: 2299–2306.
Wang, Z., Cao, Y., Albino, P., Zeff, R. A., Houghton, A. N. & Ferrone, S. (1993). Lack of HLA class I antigen expression by melanoma cell SK-MEL-33 caused by a reading frameshift in β2-microglobulin messenger RNA. J Clin Invest 91: 684–692.
Wang, Z., Margulies, D., Hicklin, J. & Ferrone, S. (1996). Molecular and functional phenotypes of melanoma cells with abnormalities in HLA class I antigen expression. Tissue Antigens 47: 382–390.
Wang, Z. G., Arienti, F., Parmiani, G. & Ferrone, S. (1998). Induction and functional characterization of β2-microglobulin (β2-μ)-free HLA class I heavy chains expressed by β2-μ-deficient human FO-1 melanoma cells. Eur J Immunol 28: 2817–2826.
Yang, S. Y. (1989). A standardized method for detection of HLA-A and HLA-B alleles by one-dimensional isoelctricfocusing (IEF) gel electrophoresis. In Immunobiology of HLA, Dupont B (ed). pp. 332–335. Springer-Verlag: New York
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Martayan, A., Fraioli, R., Giorda, E. et al. Biosynthesis of HLA-C heavy chains in melanoma cells with multiple defects in the expression of HLA-A, -B, -C molecules. Br J Cancer 80, 639–649 (1999). https://doi.org/10.1038/sj.bjc.6690405
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690405
Keywords
This article is cited by
-
HLA-dependent tumour development: a role for tumour associate macrophages?
Journal of Translational Medicine (2013)
-
KIR gene variability in cutaneous malignant melanoma: influence of KIR2D/HLA-C pairings on disease susceptibility and prognosis
Immunogenetics (2013)
-
HLA-C and HIV-1: friends or foes?
Retrovirology (2012)