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The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Jan 1;177(1):201–205. doi: 10.1084/jem.177.1.201

Tumorigenicity conferred to lymphoma mutant by major histocompatibility complex-encoded transporter gene

PMCID: PMC2190880  PMID: 8418201

Abstract

Presentation of antigenic peptides by major histocompatibility complex (MHC) class I molecules requires MHC-encoded molecules of the adenosine triphosphate binding cassette (ABC) family. Defects in these proteins represent a potential risk, since they are essential links in the machinery of T cell-mediated surveillance which continuously scrutinizes peptide samples of cellular proteins. Nevertheless, transfection of the mouse lymphoma mutant RMA-S with the rat ABC gene mtp2a (homologue to mouse HAM2 and human RING11), commonly termed TAP-2 genes, led to a marked increase in tumor outgrowth potential in vivo. This occurred despite restored antigen presentation and sensitivity to cytotoxic T lymphocytes, and was found to be due to escape from natural killer (NK) cell-mediated rejection. It has previously been proposed that adequate expression of self-MHC class I is one important mechanism to avoid elimination by NK cells. Our data argue that a defect in the machinery responsible for processing and loading of peptides into MHC class I molecules is sufficient to render cells sensitive to elimination by NK cells. The latter thus appear to function as a surveillance of the peptide surveillance machinery.

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Selected References

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  1. Attaya M., Jameson S., Martinez C. K., Hermel E., Aldrich C., Forman J., Lindahl K. F., Bevan M. J., Monaco J. J. Ham-2 corrects the class I antigen-processing defect in RMA-S cells. Nature. 1992 Feb 13;355(6361):647–649. doi: 10.1038/355647a0. [DOI] [PubMed] [Google Scholar]
  2. Chadwick B. S., Miller R. G. Hybrid resistance in vitro. Possible role of both class I MHC and self peptides in determining the level of target cell sensitivity. J Immunol. 1992 Apr 1;148(7):2307–2313. [PubMed] [Google Scholar]
  3. Deverson E. V., Gow I. R., Coadwell W. J., Monaco J. J., Butcher G. W., Howard J. C. MHC class II region encoding proteins related to the multidrug resistance family of transmembrane transporters. Nature. 1990 Dec 20;348(6303):738–741. doi: 10.1038/348738a0. [DOI] [PubMed] [Google Scholar]
  4. Elliott T. How do peptides associate with MHC class I molecules? Immunol Today. 1991 Nov;12(11):386–388. doi: 10.1016/0167-5699(91)90134-f. [DOI] [PubMed] [Google Scholar]
  5. Gidlund M., Orn A., Wigzell H., Senik A., Gresser I. Enhanced NK cell activity in mice injected with interferon and interferon inducers. Nature. 1978 Jun 29;273(5665):759–761. doi: 10.1038/273759a0. [DOI] [PubMed] [Google Scholar]
  6. Hosken N. A., Bevan M. J. An endogenous antigenic peptide bypasses the class I antigen presentation defect in RMA-S. J Exp Med. 1992 Mar 1;175(3):719–729. doi: 10.1084/jem.175.3.719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Höglund P., Glas R., Ohlén C., Ljunggren H. G., Kärre K. Alteration of the natural killer repertoire in H-2 transgenic mice: specificity of rapid lymphoma cell clearance determined by the H-2 phenotype of the target. J Exp Med. 1991 Aug 1;174(2):327–334. doi: 10.1084/jem.174.2.327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Julius M. H., Simpson E., Herzenberg L. A. A rapid method for the isolation of functional thymus-derived murine lymphocytes. Eur J Immunol. 1973 Oct;3(10):645–649. doi: 10.1002/eji.1830031011. [DOI] [PubMed] [Google Scholar]
  9. Karp D. R., Teletski C. L., Scholl P., Geha R., Long E. O. The alpha 1 domain of the HLA-DR molecule is essential for high-affinity binding of the toxic shock syndrome toxin-1. Nature. 1990 Aug 2;346(6283):474–476. doi: 10.1038/346474a0. [DOI] [PubMed] [Google Scholar]
  10. Kelly A., Powis S. H., Kerr L. A., Mockridge I., Elliott T., Bastin J., Uchanska-Ziegler B., Ziegler A., Trowsdale J., Townsend A. Assembly and function of the two ABC transporter proteins encoded in the human major histocompatibility complex. Nature. 1992 Feb 13;355(6361):641–644. doi: 10.1038/355641a0. [DOI] [PubMed] [Google Scholar]
  11. Kärre K., Ljunggren H. G., Piontek G., Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature. 1986 Feb 20;319(6055):675–678. doi: 10.1038/319675a0. [DOI] [PubMed] [Google Scholar]
  12. Ljunggren H. G., Kärre K. Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism. J Exp Med. 1985 Dec 1;162(6):1745–1759. doi: 10.1084/jem.162.6.1745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ljunggren H. G., Ohlén C., Höglund P., Yamasaki T., Klein G., Kärre K. Afferent and efferent cellular interactions in natural resistance directed against MHC class I deficient tumor grafts. J Immunol. 1988 Jan 15;140(2):671–678. [PubMed] [Google Scholar]
  14. Ljunggren H. G., Stam N. J., Ohlén C., Neefjes J. J., Höglund P., Heemels M. T., Bastin J., Schumacher T. N., Townsend A., Kärre K. Empty MHC class I molecules come out in the cold. Nature. 1990 Aug 2;346(6283):476–480. doi: 10.1038/346476a0. [DOI] [PubMed] [Google Scholar]
  15. Ljunggren H. G., Sturmhöfel K., Wolpert E., Hämmerling G. J., Kärre K. Transfection of beta 2-microglobulin restores IFN-mediated protection from natural killer cell lysis in YAC-1 lymphoma variants. J Immunol. 1990 Jul 1;145(1):380–386. [PubMed] [Google Scholar]
  16. Ljunggren H. G., Yamasaki T., Collins P., Klein G., Kärre K. Selective acceptance of MHC class I-deficient tumor grafts in the brain. J Exp Med. 1988 Feb 1;167(2):730–735. doi: 10.1084/jem.167.2.730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Monaco J. J., Cho S., Attaya M. Transport protein genes in the murine MHC: possible implications for antigen processing. Science. 1990 Dec 21;250(4988):1723–1726. doi: 10.1126/science.2270487. [DOI] [PubMed] [Google Scholar]
  18. Ohlén C., Kling G., Höglund P., Hansson M., Scangos G., Bieberich C., Jay G., Kärre K. Prevention of allogeneic bone marrow graft rejection by H-2 transgene in donor mice. Science. 1989 Nov 3;246(4930):666–668. doi: 10.1126/science.2814488. [DOI] [PubMed] [Google Scholar]
  19. Powis S. J., Deverson E. V., Coadwell W. J., Ciruela A., Huskisson N. S., Smith H., Butcher G. W., Howard J. C. Effect of polymorphism of an MHC-linked transporter on the peptides assembled in a class I molecule. Nature. 1992 May 21;357(6375):211–215. doi: 10.1038/357211a0. [DOI] [PubMed] [Google Scholar]
  20. Powis S. J., Townsend A. R., Deverson E. V., Bastin J., Butcher G. W., Howard J. C. Restoration of antigen presentation to the mutant cell line RMA-S by an MHC-linked transporter. Nature. 1991 Dec 19;354(6354):528–531. doi: 10.1038/354528a0. [DOI] [PubMed] [Google Scholar]
  21. Rock K. L., Gamble S., Rothstein L., Gramm C., Benacerraf B. Dissociation of beta 2-microglobulin leads to the accumulation of a substantial pool of inactive class I MHC heavy chains on the cell surface. Cell. 1991 May 17;65(4):611–620. doi: 10.1016/0092-8674(91)90093-e. [DOI] [PubMed] [Google Scholar]
  22. Rock K. L., Gramm C., Benacerraf B. Low temperature and peptides favor the formation of class I heterodimers on RMA-S cells at the cell surface. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4200–4204. doi: 10.1073/pnas.88.10.4200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rötzschke O., Falk K., Faath S., Rammensee H. G. On the nature of peptides involved in T cell alloreactivity. J Exp Med. 1991 Nov 1;174(5):1059–1071. doi: 10.1084/jem.174.5.1059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Schumacher T. N., Heemels M. T., Neefjes J. J., Kast W. M., Melief C. J., Ploegh H. L. Direct binding of peptide to empty MHC class I molecules on intact cells and in vitro. Cell. 1990 Aug 10;62(3):563–567. doi: 10.1016/0092-8674(90)90020-f. [DOI] [PubMed] [Google Scholar]
  25. Shimizu Y., DeMars R. Demonstration by class I gene transfer that reduced susceptibility of human cells to natural killer cell-mediated lysis is inversely correlated with HLA class I antigen expression. Eur J Immunol. 1989 Mar;19(3):447–451. doi: 10.1002/eji.1830190306. [DOI] [PubMed] [Google Scholar]
  26. Spies T., Bresnahan M., Bahram S., Arnold D., Blanck G., Mellins E., Pious D., DeMars R. A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway. Nature. 1990 Dec 20;348(6303):744–747. doi: 10.1038/348744a0. [DOI] [PubMed] [Google Scholar]
  27. Spies T., Cerundolo V., Colonna M., Cresswell P., Townsend A., DeMars R. Presentation of viral antigen by MHC class I molecules is dependent on a putative peptide transporter heterodimer. Nature. 1992 Feb 13;355(6361):644–646. doi: 10.1038/355644a0. [DOI] [PubMed] [Google Scholar]
  28. Spies T., DeMars R. Restored expression of major histocompatibility class I molecules by gene transfer of a putative peptide transporter. Nature. 1991 May 23;351(6324):323–324. doi: 10.1038/351323a0. [DOI] [PubMed] [Google Scholar]
  29. Storkus W. J., Alexander J., Payne J. A., Dawson J. R., Cresswell P. Reversal of natural killing susceptibility in target cells expressing transfected class I HLA genes. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2361–2364. doi: 10.1073/pnas.86.7.2361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Townsend A., Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol. 1989;7:601–624. doi: 10.1146/annurev.iy.07.040189.003125. [DOI] [PubMed] [Google Scholar]
  31. Townsend A., Elliott T., Cerundolo V., Foster L., Barber B., Tse A. Assembly of MHC class I molecules analyzed in vitro. Cell. 1990 Jul 27;62(2):285–295. doi: 10.1016/0092-8674(90)90366-m. [DOI] [PubMed] [Google Scholar]
  32. Townsend A., Ohlén C., Bastin J., Ljunggren H. G., Foster L., Kärre K. Association of class I major histocompatibility heavy and light chains induced by viral peptides. Nature. 1989 Aug 10;340(6233):443–448. doi: 10.1038/340443a0. [DOI] [PubMed] [Google Scholar]
  33. Trowsdale J., Hanson I., Mockridge I., Beck S., Townsend A., Kelly A. Sequences encoded in the class II region of the MHC related to the 'ABC' superfamily of transporters. Nature. 1990 Dec 20;348(6303):741–744. doi: 10.1038/348741a0. [DOI] [PubMed] [Google Scholar]
  34. Yang Y., Früh K., Chambers J., Waters J. B., Wu L., Spies T., Peterson P. A. Major histocompatibility complex (MHC)-encoded HAM2 is necessary for antigenic peptide loading onto class I MHC molecules. J Biol Chem. 1992 Jun 15;267(17):11669–11672. [PubMed] [Google Scholar]

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