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. 1994 Feb 1;179(2):681–694. doi: 10.1084/jem.179.2.681

The invariant chain is required for intracellular transport and function of major histocompatibility complex class II molecules

PMCID: PMC2191389  PMID: 8294875

Abstract

The major histocompatibility complex (MHC) class II-associated invariant chain (Ii) is thought to act as a chaperone that assists class II during folding, assembly, and transport. To define more precisely the role of Ii chain in regulating class II function, we have investigated in detail the biosynthesis, transport, and intracellular distribution of class II molecules in splenocytes from mice bearing a deletion of the Ii gene. As observed previously, the absence of Ii chain caused significant reduction in both class II-restricted antigen presentation and expression of class II molecules at the cell surface because of the intracellular accumulation of alpha and beta chains. Whereas much of the newly synthesized MHC molecules enter a high molecular weight aggregate characteristic of misfolded proteins, most of the alpha and beta chains form dimers and acquire epitopes characteristic of properly folded complexes. Although the complexes do not bind endogenously processed peptides, class II molecules that reach the surface are competent to bind peptides added to the medium, further demonstrating that at least some of the complexes fold properly. Similar to misfolded proteins, however, the alpha and beta chains are poorly terminally glycosylated, suggesting that they fail to reach the Golgi complex. As demonstrated by double label confocal and electron microscope immunocytochemistry, class II molecules were found in a subcompartment of the endoplasmic reticulum and in a population of small nonlysosomal vesicles possibly corresponding to the intermediate compartment or cis-Golgi network. Thus, although alpha and beta chains can fold and form dimers on their own, the absence of Ii chain causes them to be recognized as "misfolded" and retained in the same compartments as bona fide misfolded proteins.

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Selected References

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  1. Anderson M. S., Miller J. Invariant chain can function as a chaperone protein for class II major histocompatibility complex molecules. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2282–2286. doi: 10.1073/pnas.89.6.2282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bakke O., Dobberstein B. MHC class II-associated invariant chain contains a sorting signal for endosomal compartments. Cell. 1990 Nov 16;63(4):707–716. doi: 10.1016/0092-8674(90)90137-4. [DOI] [PubMed] [Google Scholar]
  3. Bhattacharya A., Dorf M. E., Springer T. A. A shared alloantigenic determinant on Ia antigens encoded by the I-A and I-E subregions: evidence for I region gene duplication. J Immunol. 1981 Dec;127(6):2488–2495. [PubMed] [Google Scholar]
  4. Bikoff E. K., Huang L. Y., Episkopou V., van Meerwijk J., Germain R. N., Robertson E. J. Defective major histocompatibility complex class II assembly, transport, peptide acquisition, and CD4+ T cell selection in mice lacking invariant chain expression. J Exp Med. 1993 Jun 1;177(6):1699–1712. doi: 10.1084/jem.177.6.1699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blum J. S., Cresswell P. Role for intracellular proteases in the processing and transport of class II HLA antigens. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3975–3979. doi: 10.1073/pnas.85.11.3975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bole D. G., Hendershot L. M., Kearney J. F. Posttranslational association of immunoglobulin heavy chain binding protein with nascent heavy chains in nonsecreting and secreting hybridomas. J Cell Biol. 1986 May;102(5):1558–1566. doi: 10.1083/jcb.102.5.1558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Braakman I., Helenius J., Helenius A. Role of ATP and disulphide bonds during protein folding in the endoplasmic reticulum. Nature. 1992 Mar 19;356(6366):260–262. doi: 10.1038/356260a0. [DOI] [PubMed] [Google Scholar]
  8. Braciale T. J., Morrison L. A., Sweetser M. T., Sambrook J., Gething M. J., Braciale V. L. Antigen presentation pathways to class I and class II MHC-restricted T lymphocytes. Immunol Rev. 1987 Aug;98:95–114. doi: 10.1111/j.1600-065x.1987.tb00521.x. [DOI] [PubMed] [Google Scholar]
  9. Germain R. N., Hendrix L. R. MHC class II structure, occupancy and surface expression determined by post-endoplasmic reticulum antigen binding. Nature. 1991 Sep 12;353(6340):134–139. doi: 10.1038/353134a0. [DOI] [PubMed] [Google Scholar]
  10. Granger B. L., Green S. A., Gabel C. A., Howe C. L., Mellman I., Helenius A. Characterization and cloning of lgp110, a lysosomal membrane glycoprotein from mouse and rat cells. J Biol Chem. 1990 Jul 15;265(20):12036–12043. [PubMed] [Google Scholar]
  11. Harding C. V., Unanue E. R. Cellular mechanisms of antigen processing and the function of class I and II major histocompatibility complex molecules. Cell Regul. 1990 Jun;1(7):499–509. doi: 10.1091/mbc.1.7.499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hauri H. P., Schweizer A. The endoplasmic reticulum-Golgi intermediate compartment. Curr Opin Cell Biol. 1992 Aug;4(4):600–608. doi: 10.1016/0955-0674(92)90078-Q. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hämmerling G. J., Moreno J. The function of the invariant chain in antigen presentation by MHC class II molecules. Immunol Today. 1990 Oct;11(10):337–340. doi: 10.1016/0167-5699(90)90132-s. [DOI] [PubMed] [Google Scholar]
  14. Janeway C. A., Jr, Conrad P. J., Lerner E. A., Babich J., Wettstein P., Murphy D. B. Monoclonal antibodies specific for Ia glycoproteins raised by immunization with activated T cells: possible role of T cellbound Ia antigens as targets of immunoregulatory T cells. J Immunol. 1984 Feb;132(2):662–667. [PubMed] [Google Scholar]
  15. Koch N., Koch S., Hämmerling G. J. Ia invariant chain detected on lymphocyte surfaces by monoclonal antibody. Nature. 1982 Oct 14;299(5884):644–645. doi: 10.1038/299644a0. [DOI] [PubMed] [Google Scholar]
  16. Lamb C. A., Cresswell P. Assembly and transport properties of invariant chain trimers and HLA-DR-invariant chain complexes. J Immunol. 1992 Jun 1;148(11):3478–3482. [PubMed] [Google Scholar]
  17. Lewis M. J., Pelham H. R. Ligand-induced redistribution of a human KDEL receptor from the Golgi complex to the endoplasmic reticulum. Cell. 1992 Jan 24;68(2):353–364. doi: 10.1016/0092-8674(92)90476-s. [DOI] [PubMed] [Google Scholar]
  18. Long E. O. Intracellular traffic and antigen processing. Immunol Today. 1989 Jul;10(7):232–234. doi: 10.1016/0167-5699(89)90259-4. [DOI] [PubMed] [Google Scholar]
  19. Lotteau V., Teyton L., Peleraux A., Nilsson T., Karlsson L., Schmid S. L., Quaranta V., Peterson P. A. Intracellular transport of class II MHC molecules directed by invariant chain. Nature. 1990 Dec 13;348(6302):600–605. doi: 10.1038/348600a0. [DOI] [PubMed] [Google Scholar]
  20. Marks M. S., Blum J. S., Cresswell P. Invariant chain trimers are sequestered in the rough endoplasmic reticulum in the absence of association with HLA class II antigens. J Cell Biol. 1990 Sep;111(3):839–855. doi: 10.1083/jcb.111.3.839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mellman I. S., Unkeless J. C. Purificaton of a functional mouse Fc receptor through the use of a monoclonal antibody. J Exp Med. 1980 Oct 1;152(4):1048–1069. doi: 10.1084/jem.152.4.1048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mellman I., Simons K. The Golgi complex: in vitro veritas? Cell. 1992 Mar 6;68(5):829–840. doi: 10.1016/0092-8674(92)90027-A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Miller J., Germain R. N. Efficient cell surface expression of class II MHC molecules in the absence of associated invariant chain. J Exp Med. 1986 Nov 1;164(5):1478–1489. doi: 10.1084/jem.164.5.1478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Monaco J. J. A molecular model of MHC class-I-restricted antigen processing. Immunol Today. 1992 May;13(5):173–179. doi: 10.1016/0167-5699(92)90122-N. [DOI] [PubMed] [Google Scholar]
  25. Moremen K. W., Touster O., Robbins P. W. Novel purification of the catalytic domain of Golgi alpha-mannosidase II. Characterization and comparison with the intact enzyme. J Biol Chem. 1991 Sep 5;266(25):16876–16885. [PubMed] [Google Scholar]
  26. Murphy D. B., Rath S., Pizzo E., Rudensky A. Y., George A., Larson J. K., Janeway C. A., Jr Monoclonal antibody detection of a major self peptide. MHC class II complex. J Immunol. 1992 Jun 1;148(11):3483–3491. [PubMed] [Google Scholar]
  27. Neefjes J. J., Stollorz V., Peters P. J., Geuze H. J., Ploegh H. L. The biosynthetic pathway of MHC class II but not class I molecules intersects the endocytic route. Cell. 1990 Apr 6;61(1):171–183. doi: 10.1016/0092-8674(90)90224-3. [DOI] [PubMed] [Google Scholar]
  28. Newcomb J. R., Cresswell P. Characterization of endogenous peptides bound to purified HLA-DR molecules and their absence from invariant chain-associated alpha beta dimers. J Immunol. 1993 Jan 15;150(2):499–507. [PubMed] [Google Scholar]
  29. Nuchtern J. G., Bonifacino J. S., Biddison W. E., Klausner R. D. Brefeldin A implicates egress from endoplasmic reticulum in class I restricted antigen presentation. Nature. 1989 May 18;339(6221):223–226. doi: 10.1038/339223a0. [DOI] [PubMed] [Google Scholar]
  30. Pelham H. R. Control of protein exit from the endoplasmic reticulum. Annu Rev Cell Biol. 1989;5:1–23. doi: 10.1146/annurev.cb.05.110189.000245. [DOI] [PubMed] [Google Scholar]
  31. Pelham H. R. The retention signal for soluble proteins of the endoplasmic reticulum. Trends Biochem Sci. 1990 Dec;15(12):483–486. doi: 10.1016/0968-0004(90)90303-s. [DOI] [PubMed] [Google Scholar]
  32. Peterson M., Miller J. Antigen presentation enhanced by the alternatively spliced invariant chain gene product p41. Nature. 1992 Jun 18;357(6379):596–598. doi: 10.1038/357596a0. [DOI] [PubMed] [Google Scholar]
  33. Peterson M., Miller J. Invariant chain influences the immunological recognition of MHC class II molecules. Nature. 1990 May 10;345(6271):172–174. doi: 10.1038/345172a0. [DOI] [PubMed] [Google Scholar]
  34. Reaves B., Wilde A., Banting G. Identification, molecular characterization and immunolocalization of an isoform of the trans-Golgi-network (TGN)-specific integral membrane protein TGN38. Biochem J. 1992 Apr 15;283(Pt 2):313–316. doi: 10.1042/bj2830313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Roche P. A., Cresswell P. Invariant chain association with HLA-DR molecules inhibits immunogenic peptide binding. Nature. 1990 Jun 14;345(6276):615–618. doi: 10.1038/345615a0. [DOI] [PubMed] [Google Scholar]
  36. Rudensky AYu, Preston-Hurlburt P., Hong S. C., Barlow A., Janeway C. A., Jr Sequence analysis of peptides bound to MHC class II molecules. Nature. 1991 Oct 17;353(6345):622–627. doi: 10.1038/353622a0. [DOI] [PubMed] [Google Scholar]
  37. Rudensky AYu, Rath S., Preston-Hurlburt P., Murphy D. B., Janeway C. A., Jr On the complexity of self. Nature. 1991 Oct 17;353(6345):660–662. doi: 10.1038/353660a0. [DOI] [PubMed] [Google Scholar]
  38. Sadegh-Nasseri S., Germain R. N. A role for peptide in determining MHC class II structure. Nature. 1991 Sep 12;353(6340):167–170. doi: 10.1038/353167a0. [DOI] [PubMed] [Google Scholar]
  39. Sekaly R. P., Tonnelle C., Strubin M., Mach B., Long E. O. Cell surface expression of class II histocompatibility antigens occurs in the absence of the invariant chain. J Exp Med. 1986 Nov 1;164(5):1490–1504. doi: 10.1084/jem.164.5.1490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Semenza J. C., Pelham H. R. Changing the specificity of the sorting receptor for luminal endoplasmic reticulum proteins. J Mol Biol. 1992 Mar 5;224(1):1–5. doi: 10.1016/0022-2836(92)90571-z. [DOI] [PubMed] [Google Scholar]
  41. Slot J. W., Geuze H. J., Gigengack S., Lienhard G. E., James D. E. Immuno-localization of the insulin regulatable glucose transporter in brown adipose tissue of the rat. J Cell Biol. 1991 Apr;113(1):123–135. doi: 10.1083/jcb.113.1.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Stern L. J., Wiley D. C. The human class II MHC protein HLA-DR1 assembles as empty alpha beta heterodimers in the absence of antigenic peptide. Cell. 1992 Feb 7;68(3):465–477. doi: 10.1016/0092-8674(92)90184-e. [DOI] [PubMed] [Google Scholar]
  43. Stockinger B., Pessara U., Lin R. H., Habicht J., Grez M., Koch N. A role of Ia-associated invariant chains in antigen processing and presentation. Cell. 1989 Feb 24;56(4):683–689. doi: 10.1016/0092-8674(89)90590-4. [DOI] [PubMed] [Google Scholar]
  44. Tokuyasu K. T. Immunochemistry on ultrathin frozen sections. Histochem J. 1980 Jul;12(4):381–403. doi: 10.1007/BF01011956. [DOI] [PubMed] [Google Scholar]
  45. 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]
  46. Viville S., Neefjes J., Lotteau V., Dierich A., Lemeur M., Ploegh H., Benoist C., Mathis D. Mice lacking the MHC class II-associated invariant chain. Cell. 1993 Feb 26;72(4):635–648. doi: 10.1016/0092-8674(93)90081-z. [DOI] [PubMed] [Google Scholar]
  47. Watts C., Davidson H. W. Endocytosis and recycling of specific antigen by human B cell lines. EMBO J. 1988 Jul;7(7):1937–1945. doi: 10.1002/j.1460-2075.1988.tb03031.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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