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. 1996 Nov 1;184(5):1747–1753. doi: 10.1084/jem.184.5.1747

Invariant chain and DM edit self-peptide presentation by major histocompatibility complex (MHC) class II molecules

PMCID: PMC2192856  PMID: 8920863

Abstract

We have studied the consequences of invariant chain (Ii) and DM expression on major histocompatibility complex (MHC) class II function. Ii has a number of discrete functions in the biology of class II, including competitive blocking of peptide binding in the endoplasmic reticulum and enhancing localization in the endocytic compartments. DM is thought to act primarily in endosomes to promote dissociation of the Ii-derived (CLIP) peptide from the class II antigen-binding pocket and subsequent peptide loading. In this study, we have evaluated the functional role of Ii and DM by examining their impact on surface expression of epitopes recognized by a large panel of alloreactive T cells. We find most epitopes studied are influenced by both Ii and DM. Most strikingly, we find that surface expression of a significant fraction of peptide-class II complexes is extinguished, rather than enhanced, by DM expression within the APC. The epitopes antagonized by DM do not appear to be specific for CLIP. Finally, we found that DM was also able to extinguish recognition of a defined peptide derived from the internally synthesized H-2Ld protein. Thus, rather than primarily serving in the removal of CLIP, DM may have a more generalized function of editing the array of peptides that are presented by class II. This editing can be either positive or negative, suggesting that DM plays a specifying role in the display of peptides presented to CD4 T cells.

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Selected References

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

  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. Bodmer H., Viville S., Benoist C., Mathis D. Diversity of endogenous epitopes bound to MHC class II molecules limited by invariant chain. Science. 1994 Mar 4;263(5151):1284–1286. doi: 10.1126/science.7510069. [DOI] [PubMed] [Google Scholar]
  4. Brooks A. G., Campbell P. L., Reynolds P., Gautam A. M., McCluskey J. Antigen presentation and assembly by mouse I-Ak class II molecules in human APC containing deleted or mutated HLA DM genes. J Immunol. 1994 Dec 15;153(12):5382–5392. [PubMed] [Google Scholar]
  5. Busch R., Mellins E. D. Developing and shedding inhibitions: how MHC class II molecules reach maturity. Curr Opin Immunol. 1996 Feb;8(1):51–58. doi: 10.1016/s0952-7915(96)80105-1. [DOI] [PubMed] [Google Scholar]
  6. Ceman S., Rudersdorf R. A., Petersen J. M., DeMars R. DMA and DMB are the only genes in the class II region of the human MHC needed for class II-associated antigen processing. J Immunol. 1995 Mar 15;154(6):2545–2556. [PubMed] [Google Scholar]
  7. Chicz R. M., Urban R. G., Gorga J. C., Vignali D. A., Lane W. S., Strominger J. L. Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J Exp Med. 1993 Jul 1;178(1):27–47. doi: 10.1084/jem.178.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cresswell P. Invariant chain structure and MHC class II function. Cell. 1996 Feb 23;84(4):505–507. doi: 10.1016/s0092-8674(00)81025-9. [DOI] [PubMed] [Google Scholar]
  9. Denzin L. K., Cresswell P. HLA-DM induces CLIP dissociation from MHC class II alpha beta dimers and facilitates peptide loading. Cell. 1995 Jul 14;82(1):155–165. doi: 10.1016/0092-8674(95)90061-6. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Fling S. P., Arp B., Pious D. HLA-DMA and -DMB genes are both required for MHC class II/peptide complex formation in antigen-presenting cells. Nature. 1994 Apr 7;368(6471):554–558. doi: 10.1038/368554a0. [DOI] [PubMed] [Google Scholar]
  12. Fung-Leung W. P., Surh C. D., Liljedahl M., Pang J., Leturcq D., Peterson P. A., Webb S. R., Karlsson L. Antigen presentation and T cell development in H2-M-deficient mice. Science. 1996 Mar 1;271(5253):1278–1281. doi: 10.1126/science.271.5253.1278. [DOI] [PubMed] [Google Scholar]
  13. Hunt D. F., Michel H., Dickinson T. A., Shabanowitz J., Cox A. L., Sakaguchi K., Appella E., Grey H. M., Sette A. Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad. Science. 1992 Jun 26;256(5065):1817–1820. doi: 10.1126/science.1319610. [DOI] [PubMed] [Google Scholar]
  14. Izumi M., Miyazawa H., Kamakura T., Yamaguchi I., Endo T., Hanaoka F. Blasticidin S-resistance gene (bsr): a novel selectable marker for mammalian cells. Exp Cell Res. 1991 Dec;197(2):229–233. doi: 10.1016/0014-4827(91)90427-v. [DOI] [PubMed] [Google Scholar]
  15. Katz J. F., Sant A. J. T cell receptor recognition of MHC class II alloantigens is highly cell type dependent. J Immunol. 1994 Feb 15;152(4):1629–1640. [PubMed] [Google Scholar]
  16. Layet C., Germain R. N. 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. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2346–2350. doi: 10.1073/pnas.88.6.2346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Loss G. E., Jr, Elias C. G., Fields P. E., Ribaudo R. K., McKisic M., Sant A. J. Major histocompatibility complex class II-restricted presentation of an internally synthesized antigen displays cell-type variability and segregates from the exogenous class II and endogenous class I presentation pathways. J Exp Med. 1993 Jul 1;178(1):73–85. doi: 10.1084/jem.178.1.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Mellins E., Kempin S., Smith L., Monji T., Pious D. A gene required for class II-restricted antigen presentation maps to the major histocompatibility complex. J Exp Med. 1991 Dec 1;174(6):1607–1615. doi: 10.1084/jem.174.6.1607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Moreno J., Vignali D. A., Nadimi F., Fuchs S., Adorini L., Hämmerling G. J. Processing of an endogenous protein can generate MHC class II-restricted T cell determinants distinct from those derived from exogenous antigen. J Immunol. 1991 Nov 15;147(10):3306–3313. [PubMed] [Google Scholar]
  21. Morris P., Shaman J., Attaya M., Amaya M., Goodman S., Bergman C., Monaco J. J., Mellins E. An essential role for HLA-DM in antigen presentation by class II major histocompatibility molecules. Nature. 1994 Apr 7;368(6471):551–554. doi: 10.1038/368551a0. [DOI] [PubMed] [Google Scholar]
  22. Nelson C. A., Petzold S. J., Unanue E. R. Identification of two distinct properties of class II major histocompatibility complex-associated peptides. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1227–1231. doi: 10.1073/pnas.90.4.1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nuchtern J. G., Biddison W. E., Klausner R. D. Class II MHC molecules can use the endogenous pathway of antigen presentation. Nature. 1990 Jan 4;343(6253):74–76. doi: 10.1038/343074a0. [DOI] [PubMed] [Google Scholar]
  24. Panina-Bordignon P., Corradin G., Roosnek E., Sette A., Lanzavecchia A. Recognition by class II alloreactive T cells of processed determinants from human serum proteins. Science. 1991 Jun 14;252(5012):1548–1550. doi: 10.1126/science.1710827. [DOI] [PubMed] [Google Scholar]
  25. Pieters J., Horstmann H., Bakke O., Griffiths G., Lipp J. Intracellular transport and localization of major histocompatibility complex class II molecules and associated invariant chain. J Cell Biol. 1991 Dec;115(5):1213–1223. doi: 10.1083/jcb.115.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pinet V., Malnati M. S., Long E. O. Two processing pathways for the MHC class II-restricted presentation of exogenous influenza virus antigen. J Immunol. 1994 May 15;152(10):4852–4860. [PubMed] [Google Scholar]
  27. Riberdy J. M., Cresswell P. The antigen-processing mutant T2 suggests a role for MHC-linked genes in class II antigen presentation. J Immunol. 1992 Apr 15;148(8):2586–2590. [PubMed] [Google Scholar]
  28. Riberdy J. M., Newcomb J. R., Surman M. J., Barbosa J. A., Cresswell P. HLA-DR molecules from an antigen-processing mutant cell line are associated with invariant chain peptides. Nature. 1992 Dec 3;360(6403):474–477. doi: 10.1038/360474a0. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Runnels H. A., Moore J. C., Jensen P. E. A structural transition in class II major histocompatibility complex proteins at mildly acidic pH. J Exp Med. 1996 Jan 1;183(1):127–136. doi: 10.1084/jem.183.1.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]
  32. Sanderson F., Kleijmeer M. J., Kelly A., Verwoerd D., Tulp A., Neefjes J. J., Geuze H. J., Trowsdale J. Accumulation of HLA-DM, a regulator of antigen presentation, in MHC class II compartments. Science. 1994 Dec 2;266(5190):1566–1569. doi: 10.1126/science.7985027. [DOI] [PubMed] [Google Scholar]
  33. Sanderson F., Thomas C., Neefjes J., Trowsdale J. Association between HLA-DM and HLA-DR in vivo. Immunity. 1996 Jan;4(1):87–96. doi: 10.1016/s1074-7613(00)80301-5. [DOI] [PubMed] [Google Scholar]
  34. Sant A. J. Endogenous antigen presentation by MHC class II molecules. Immunol Res. 1994;13(4):253–267. doi: 10.1007/BF02935617. [DOI] [PubMed] [Google Scholar]
  35. Sant A. J., Germain R. N. Intracellular competition for component chains determines class II MHC cell surface phenotype. Cell. 1989 Jun 2;57(5):797–805. doi: 10.1016/0092-8674(89)90794-0. [DOI] [PubMed] [Google Scholar]
  36. Sant A. J., Miller J. MHC class II antigen processing: biology of invariant chain. Curr Opin Immunol. 1994 Feb;6(1):57–63. doi: 10.1016/0952-7915(94)90034-5. [DOI] [PubMed] [Google Scholar]
  37. Schaiff W. T., Hruska K. A., Jr, Bono C., Shuman S., Schwartz B. D. Invariant chain influences post-translational processing of HLA-DR molecules. J Immunol. 1991 Jul 15;147(2):603–608. [PubMed] [Google Scholar]
  38. Sette A., Ceman S., Kubo R. T., Sakaguchi K., Appella E., Hunt D. F., Davis T. A., Michel H., Shabanowitz J., Rudersdorf R. Invariant chain peptides in most HLA-DR molecules of an antigen-processing mutant. Science. 1992 Dec 11;258(5089):1801–1804. doi: 10.1126/science.1465617. [DOI] [PubMed] [Google Scholar]
  39. Sherman M. A., Weber D. A., Jensen P. E. DM enhances peptide binding to class II MHC by release of invariant chain-derived peptide. Immunity. 1995 Aug;3(2):197–205. doi: 10.1016/1074-7613(95)90089-6. [DOI] [PubMed] [Google Scholar]
  40. Sloan V. S., Cameron P., Porter G., Gammon M., Amaya M., Mellins E., Zaller D. M. Mediation by HLA-DM of dissociation of peptides from HLA-DR. Nature. 1995 Jun 29;375(6534):802–806. doi: 10.1038/375802a0. [DOI] [PubMed] [Google Scholar]
  41. Stebbins C. C., Loss G. E., Jr, Elias C. G., Chervonsky A., Sant A. J. The requirement for DM in class II-restricted antigen presentation and SDS-stable dimer formation is allele and species dependent. J Exp Med. 1995 Jan 1;181(1):223–234. doi: 10.1084/jem.181.1.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. 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]
  43. Wolf P. R., Ploegh H. L. How MHC class II molecules acquire peptide cargo: biosynthesis and trafficking through the endocytic pathway. Annu Rev Cell Dev Biol. 1995;11:267–306. doi: 10.1146/annurev.cb.11.110195.001411. [DOI] [PubMed] [Google Scholar]

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