Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Mar 15;88(6):2346–2350. doi: 10.1073/pnas.88.6.2346

Invariant chain promotes egress of poorly expressed, haplotype-mismatched class II major histocompatibility complex A alpha A beta dimers from the endoplasmic reticulum/cis-Golgi compartment.

C Layet 1, R N Germain 1
PMCID: PMC51228  PMID: 1900941

Abstract

Invariant chain (Ii) is a nonpolymorphic, non-major histocompatibility complex (MHC)-encoded glycoprotein that rapidly associates with newly synthesized class II MHC alpha and beta chains in the rough endoplasmic reticulum. This oligomerization of Ii, alpha, and beta and their cotransport within the cell led to speculation that Ii was an essential alpha beta transport protein. However, direct tests failed to show an absolute requirement for Ii in class II MHC molecule transport. More recently, it has become clear that different class II alpha beta chain combinations vary greatly in their efficiency of cell-surface expression, based largely on the allelic origin of the alpha and beta amino-terminal regions. Because the previous tests of Ii for a role in class II molecule expression utilized efficiently expressed alpha beta combinations, we have reexamined this question with several haplotype-mismatched murine A alpha and A beta chain combinations of various potentials for cell-surface expression. Using a transient expression assay in Ii-negative COS cells, we find that many inefficiently expressed alpha beta combinations show marked augmentation of surface expression upon cosynthesis of Ii. This effect is absent or minimal with evolutionarily coselected, haplotype-matched chains that give efficient expression alone. Biochemical studies show that at least one component of the Ii effect is an increased egress of already formed alpha beta dimers from the rough endoplasmic reticulum/cis-Golgi. We suggest that these results reflect the interaction of Ii with the peptide-binding domain of the poorly expressed class II molecules, either aiding in maintenance of a transportable conformation or competing with endoplasmic reticulum retention proteins, and thus enhancing movement to the cell surface. These results suggest a complex and variable role for trans-associated alpha and beta chains in the immune responses of MHC heterozygotes and provide a method for examining Ii interaction with class II MHC molecules independent of measurement of peptide presentation to T cells.

Full text

PDF
2346

Images in this article

2349Image
on p.2349
2349Image
on p.2349

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Braunstein N. S., Germain R. N. Allele-specific control of Ia molecule surface expression and conformation: implications for a general model of Ia structure-function relationships. Proc Natl Acad Sci U S A. 1987 May;84(9):2921–2925. doi: 10.1073/pnas.84.9.2921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Braunstein N. S., Germain R. N., Loney K., Berkowitz N. Structurally interdependent and independent regions of allelic polymorphism in class II MHC molecules. Implications for Ia function and evolution. J Immunol. 1990 Sep 15;145(6):1635–1645. [PubMed] [Google Scholar]
  3. Brown J. H., Jardetzky T., Saper M. A., Samraoui B., Bjorkman P. J., Wiley D. C. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature. 1988 Apr 28;332(6167):845–850. doi: 10.1038/332845a0. [DOI] [PubMed] [Google Scholar]
  4. Buerstedde J. M., Pease L. R., Nilson A. E., Bell M. P., Chase C., Buerstedde G., McKean D. J. Regulation of murine MHC class II molecule expression. Identification of A beta residues responsible for allele-specific cell surface expression. J Exp Med. 1988 Sep 1;168(3):823–837. doi: 10.1084/jem.168.3.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Claesson-Welsh L., Peterson P. A. Implications of the invariant gamma-chain on the intracellular transport of class II histocompatibility antigens. J Immunol. 1985 Nov;135(5):3551–3557. [PubMed] [Google Scholar]
  6. Cullen S. E., Schwartz B. D. An improved method for isolation of H-2 and Ia alloantigens with immunoprecipitation induced by protein A-bearing staphylococci. J Immunol. 1976 Jul;117(1):136–142. [PubMed] [Google Scholar]
  7. Dornmair K., Rothenhäusler B., McConnell H. M. Structural intermediates in the reactions of antigenic peptides with MHC molecules. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 1):409–416. doi: 10.1101/sqb.1989.054.01.050. [DOI] [PubMed] [Google Scholar]
  8. Germain R. N., Bentley D. M., Quill H. Influence of allelic polymorphism on the assembly and surface expression of class II MHC (Ia) molecules. Cell. 1985 Nov;43(1):233–242. doi: 10.1016/0092-8674(85)90028-5. [DOI] [PubMed] [Google Scholar]
  9. Germain R. N. Immunology. The ins and outs of antigen processing and presentation. Nature. 1986 Aug 21;322(6081):687–689. doi: 10.1038/322687a0. [DOI] [PubMed] [Google Scholar]
  10. Gluzman Y. SV40-transformed simian cells support the replication of early SV40 mutants. Cell. 1981 Jan;23(1):175–182. doi: 10.1016/0092-8674(81)90282-8. [DOI] [PubMed] [Google Scholar]
  11. Green J., Griffiths G., Louvard D., Quinn P., Warren G. Passage of viral membrane proteins through the Golgi complex. J Mol Biol. 1981 Nov 15;152(4):663–698. doi: 10.1016/0022-2836(81)90122-4. [DOI] [PubMed] [Google Scholar]
  12. Jones P. P., Murphy D. B., Hewgill D., McDevitt H. O. Detection of a common polypeptide chain in I--A and I--E sub-region immunoprecipitates. Mol Immunol. 1979 Jan;16(1):51–60. doi: 10.1016/0161-5890(79)90027-0. [DOI] [PubMed] [Google Scholar]
  13. Koch N., Harris A. W. Differential expression of the invariant chain in mouse tumor cells: relationship to B lymphoid development. J Immunol. 1984 Jan;132(1):12–15. [PubMed] [Google Scholar]
  14. Landias D., Beck B. N., Buerstedde J. M., Degraw S., Klein D., Koch N., Murphy D., Pierres M., Tada T., Yamamoto K. The assignment of chain specificities for anti-Ia monoclonal antibodies using L cell transfectants. J Immunol. 1986 Nov 1;137(9):3002–3005. [PubMed] [Google Scholar]
  15. Lechler R. I., Sant A. J., Braunstein N. S., Sekaly R., Long E., Germain R. N. Cell surface expression of hybrid murine/human MHC class II beta alpha dimers. Key influence of residues in the amino-terminal portion of the beta 1 domain. J Immunol. 1990 Jan 1;144(1):329–333. [PubMed] [Google Scholar]
  16. Lippincott-Schwartz J., Donaldson J. G., Schweizer A., Berger E. G., Hauri H. P., Yuan L. C., Klausner R. D. Microtubule-dependent retrograde transport of proteins into the ER in the presence of brefeldin A suggests an ER recycling pathway. Cell. 1990 Mar 9;60(5):821–836. doi: 10.1016/0092-8674(90)90096-w. [DOI] [PubMed] [Google Scholar]
  17. Lopata M. A., Cleveland D. W., Sollner-Webb B. High level transient expression of a chloramphenicol acetyl transferase gene by DEAE-dextran mediated DNA transfection coupled with a dimethyl sulfoxide or glycerol shock treatment. Nucleic Acids Res. 1984 Jul 25;12(14):5707–5717. doi: 10.1093/nar/12.14.5707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Machamer C. E., Cresswell P. Monensin prevents terminal glycosylation of the N- and O-linked oligosaccharides of the HLA-DR-associated invariant chain and inhibits its dissociation from the alpha-beta chain complex. Proc Natl Acad Sci U S A. 1984 Mar;81(5):1287–1291. doi: 10.1073/pnas.81.5.1287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Malissen B., Steinmetz M., McMillan M., Pierres M., Hood L. Expression of I-Ak class II genes in mouse L cells after DNA-mediated gene transfer. 1983 Sep 29-Oct 5Nature. 305(5933):440–443. doi: 10.1038/305440a0. [DOI] [PubMed] [Google Scholar]
  20. McMillan M., Frelinger J. A., Jones P. P., Murphy D. B., McDevitt H. O., Hood L. Structure of murine Ia antigens. Two dimensional electrophoretic analyses and high pressure liquid chromatography tryptic peptide maps of products of the I-A and I-E subregions and of an associated invariant polypeptide. J Exp Med. 1981 Apr 1;153(4):936–950. doi: 10.1084/jem.153.4.936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Murphy D. B., Jones P. P., Loken M. R., McDevitt H. O. Interaction between I region loci influences the expression of a cell surface Ia antigen. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5404–5408. doi: 10.1073/pnas.77.9.5404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Norcross M. A., Bentley D. M., Margulies D. H., Germain R. N. Membrane Ia expression and antigen-presenting accessory cell function of L cells transfected with class II major histocompatibility complex genes. J Exp Med. 1984 Nov 1;160(5):1316–1337. doi: 10.1084/jem.160.5.1316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Pelham H. R. Evidence that luminal ER proteins are sorted from secreted proteins in a post-ER compartment. EMBO J. 1988 Apr;7(4):913–918. doi: 10.1002/j.1460-2075.1988.tb02896.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. 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]
  27. Ronchese F., Brown M. A., Germain R. N. Structure-function analysis of the Abm12 beta mutation using site-directed mutagenesis and DNA-mediated gene transfer. J Immunol. 1987 Jul 15;139(2):629–638. [PubMed] [Google Scholar]
  28. Rothman J. E. Polypeptide chain binding proteins: catalysts of protein folding and related processes in cells. Cell. 1989 Nov 17;59(4):591–601. doi: 10.1016/0092-8674(89)90005-6. [DOI] [PubMed] [Google Scholar]
  29. Sant A. J., Braunstein N. S., Germain R. N. Predominant role of amino-terminal sequences in dictating efficiency of class II major histocompatibility complex alpha beta dimer expression. Proc Natl Acad Sci U S A. 1987 Nov;84(22):8065–8069. doi: 10.1073/pnas.84.22.8065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schlauder G. G., Bell M. P., Beck B. N., Nilson A., McKean D. J. The structure-function relationship of I-A molecules: a biochemical analysis of I-A polypeptides from mutant antigen-presenting cells and evidence of preferential association of allelic forms. J Immunol. 1985 Sep;135(3):1945–1954. [PubMed] [Google Scholar]
  31. Schneider F. J., Opel B., Ballhausen W., Henkes W., Steinlein P., Reske K. Synthesis and expression of MHC class II molecules in the absence of attached invariant chains by recombinant-interferon-gamma-activated bone-marrow-derived macrophages. Eur J Immunol. 1987 Sep;17(9):1235–1242. doi: 10.1002/eji.1830170904. [DOI] [PubMed] [Google Scholar]
  32. Schwartz R. H. Immune response (Ir) genes of the murine major histocompatibility complex. Adv Immunol. 1986;38:31–201. doi: 10.1016/s0065-2776(08)60006-1. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Simonis S., Miller J., Cullen S. E. The role of the Ia-invariant chain complex in the posttranslational processing and transport of Ia and invariant chain glycoproteins. J Immunol. 1989 Dec 1;143(11):3619–3625. [PubMed] [Google Scholar]
  35. Swiedler S. J., Freed J. H., Tarentino A. L., Plummer T. H., Jr, Hart G. W. Oligosaccharide microheterogeneity of the murine major histocompatibility antigens. Reproducible site-specific patterns of sialylation and branching in asparagine-linked oligosaccharides. J Biol Chem. 1985 Apr 10;260(7):4046–4054. [PubMed] [Google Scholar]
  36. Teyton L., O'Sullivan D., Dickson P. W., Lotteau V., Sette A., Fink P., Peterson P. A. Invariant chain distinguishes between the exogenous and endogenous antigen presentation pathways. Nature. 1990 Nov 1;348(6296):39–44. doi: 10.1038/348039a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES