Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Upregulation of the CLIP self peptide on mature dendritic cells antagonizes T helper type 1 polarization

Nature Immunology volume 5, pages 909–918 (2004)Cite this article

Abstract

Dendritic cells (DCs) initiate and regulate immunity against foreign and self antigens. Here we identified more than 200 individual major histocompatibility complex class II–associated peptides on human DCs and found that mature DCs selectively upregulated the self peptide CLIP. CLIP cosegregated together with foreign antigenic peptides in tetraspan microdomains on the surface and localized to DC–T cell synapses. The increased representation of CLIP–major histocompatibility complex class II complexes favored polarization of autologous naive T cells toward the nonpolarized and T helper type 2 (TH2) phenotype. There was also a considerably higher TH2/TH1 ratio in H2-DM-deficient mice, which have a CLIPhi phenotype, in contrast to wild-type, CLIPlo mice. Thus, the self peptide CLIP on DCs qualifies as an endogenous regulator in priming of T helper cells by antagonizing the polarization toward the TH1 phenotype.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Accumulation of CLIP–MHC class II complexes on mature DCs.
Figure 2: Downregulation of HLA-DM and its activity during maturation.
Figure 3: Copresentation of CLIP and antigenic peptides.
Figure 4: CLIP-MHC II complexes cluster in the central area of the synapse formed between mature DCs and Jurkat T cells.
Figure 5: CLIP is a constituent of CDw78 microdomains of DCs and tonsil APCs.
Figure 6: CLIP on DCs influences polarization of naive CD4+ T cells.
Figure 7: Endogenous CLIP effects on T cell polarization in vivo.

Similar content being viewed by others

References

  1. Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).

    Article  CAS  Google Scholar 

  2. Cresswell, P. Invariant chain structure and MHC class II function. Cell 84, 505–507 (1996).

    Article  CAS  Google Scholar 

  3. 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 360, 474–477 (1992).

    Article  CAS  Google Scholar 

  4. Kropshofer, H., Hammerling, G.J. & Vogt, A.B. The impact of the non-classical MHC proteins HLA-DM and HLA-DO on loading of MHC class II molecules. Immunol. Rev. 172, 267–278 (1999).

    Article  CAS  Google Scholar 

  5. Buus, S., Sette, A., Colon, S.M. & Grey, H.M. Autologous peptides constitutively occupy the antigen binding site on Ia. Science 242, 1045–1047 (1988).

    Article  CAS  Google Scholar 

  6. Heath, W.R. & Carbone, F.R. Cross-presentation, dendritic cells, tolerance and immunity. Annu. Rev. Immunol. 19, 47–64 (2001).

    Article  CAS  Google Scholar 

  7. Brocker, T. Survival of mature CD4 T lymphocytes is dependent on major histocompatibility complex class II-expressing dendritic cells. J. Exp. Med. 186, 1223–1232 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Viret, C., Wong, F.S. & Janeway, C.A., Jr. Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition. Immunity 10, 559–568 (1999).

    Article  CAS  Google Scholar 

  9. Wulfing, C. et al. Costimulation and endogenous MHC ligands contribute to T cell recognition. Nat. Immunol. 3, 42–47 (2002).

    Article  CAS  Google Scholar 

  10. Stefanova, I., Dorfman, J.R. & Germain, R.N. Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420, 429–434 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Bhandoola, A. et al. Peripheral expression of self-MHC-II influences the reactivity and self-tolerance of mature CD4+ T cells: evidence from a lymphopenic T cell model. Immunity 17, 425–436 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Constant, S.L. & Bottomly, K. Induction of TH1 and TH2 CD4+ T cell responses: the alternative approach. Annu. Rev. Immunol. 15, 297–322 (1997).

    Article  CAS  Google Scholar 

  13. Vogt, A.B., Spindeldreher, S. & Kropshofer, H. Clustering of MHC-peptide complexes prior to their engagement in the immunological synapse: lipid raft and tetraspan microdomains. Immunol. Rev. 189, 136–151 (2002).

    Article  CAS  Google Scholar 

  14. Dongre, A.R. et al. In vivo MHC class II presentation of cytosolic proteins revealed by rapid automated tandem mass spectrometry and functional analyses. Eur. J. Immunol. 31, 1485–1494 (2001).

    Article  CAS  Google Scholar 

  15. Fung-Leung, W.P. et al. Antigen presentation and T cell development in H2-M-deficient mice. Science 271, 1278–1281 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Martin, W.D. et al. H2-M mutant mice are defective in the peptide loading of class II molecules, antigen presentation, and T cell repertoire selection. Cell 84, 543–550 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Miyazaki, T. et al. Mice lacking H2-M complexes, enigmatic elements of the MHC class II peptide-loading pathway. Cell 84, 531–541 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Chen, X. et al. Regulated expression of human histocompatibility leukocyte antigen (HLA)-DO during antigen-dependent and antigen-independent phases of B cell development. J. Exp. Med. 195, 1053–1062 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Glazier, K.S. et al. Germinal center B cells regulate their capability to present antigen by modulation of HLA-DO. J. Exp. Med. 195, 1063–1069 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Denzin, L.K., Sant'Angelo, D.B., Hammond, C., Surman, M.J. & Cresswell, P. Negative regulation by HLA-DO of MHC class II-restricted antigen processing. Science 278, 106–109 (1997).

    Article  CAS  Google Scholar 

  21. Kropshofer, H. et al. A role for HLA-DO as a co-chaperone of HLA-DM in peptide loading of MHC class II molecules. EMBO J. 17, 2971–2981 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Monks, C.R., Freiberg, B.A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 (1998).

    Article  CAS  Google Scholar 

  23. Bromley, S.K. et al. The immunological synapse and CD28-CD80 interactions. Nat. Immunol. 2, 1159–1166 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Kropshofer, H. et al. Tetraspan microdomains distinct from lipid rafts enrich select peptide-MHC class II complexes. Nat. Immunol. 3, 61–68 (2002).

    Article  CAS  Google Scholar 

  25. Mittelbrunn, M., Yanez-Mo, M., Sancho, D., Ursa, S. & Sanchez-Madrid, F. Cutting edge: dynamic redistribution of tetraspanin CD81 at the central zone of the immune synapse in both T lymphocytes and APC. J. Immunol. 169, 6691–6695 (2002).

    Article  CAS  Google Scholar 

  26. Langenkamp, A., Messi, M., Lanzavecchia, A. & Sallusto, F. Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat. Immunol. 1, 311–316 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Barnden, M.J., Allison, J., Heath, W.R. & Carbone, F.R. Defective TCR expression in transgenic mice constructed using cDNA-based α- and β-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998).

    Article  CAS  Google Scholar 

  28. Goldrath, A.W. & Bevan, M.J. Selecting and maintaining a diverse T-cell repertoire. Nature 402, 255–262 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Germain, R.N., Stefanova, I. & Dorfman, J. Self-recognition and the regulation of CD4+ T cell survival. Adv. Exp. Med. Biol. 512, 97–105 (2002).

    Article  CAS  Google Scholar 

  30. Kropshofer, H., Arndt, S.O., Moldenhauer, G., Hammerling, G.J. & Vogt, A.B. HLA-DM acts as a molecular chaperone and rescues empty HLA-DR molecules at lysosomal pH. Immunity 6, 293–302 (1997).

    Article  CAS  Google Scholar 

  31. Alfonso, C. & Karlsson, L. Nonclassical MHC class II molecules. Annu. Rev. Immunol. 18, 113–142 (2000).

    Article  CAS  Google Scholar 

  32. Arneson, L.S., Peterson, M. & Sant, A.J. The MHC class II molecule I-Ag7 exists in alternate conformations that are peptide-dependent. J. Immunol. 165, 2059–2067 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Zhu, Y., Rudensky, A.Y., Corper, A.L., Teyton, L. & Wilson, I.A. Crystal structure of MHC class II I-Ab in complex with a human CLIP peptide: prediction of an I-Ab peptide-binding motif. J. Molec. Biol. 326, 1157–1174 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Hosken, N.A., Shibuya, K., Heath, A.W., Murphy, K.M. & O'Garra, A. The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model. J. Exp. Med. 182, 1579–1584 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Irvine, D.J., Purbhoo, M.A., Krogsgaard, M. & Davis, M. Direct observation of ligand recognition by T cells. Nature 419, 845–849 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Li, Q.-J. et al. CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse. Nat. Immunol. 5, 791–799 (2004).

    Article  CAS  Google Scholar 

  37. Wu, L.C., Tuot, D.S., Lyons, D.S., Garcia, K.C. & Davis, M.M. Two-step binding mechanism for T-cell receptor recognition of peptide-MHC. Nature 418, 552–556 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Topilski, I., Harmelin, A., Flavell, R.A., Levo, Y. & Shachar, I. Preferential Th1 immune response in invariant chain-deficient mice. J. Immunol. 168, 1610–1617 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Chaturvedi, P., Hengeveld, R., Zechel, M.A., Lee-Chan, E. & Singh, B. the functional role of class II-associated invariant chain peptide (CLIP) in its ability to variably modulate immune responses. Internat. Immunol. 12, 757–765 (2000).

    Article  CAS  Google Scholar 

  40. Patil, N.S. et al. Rheumatoid arthritis (RA)-associated HLA-DR alleles form less stable complexes with class II-associated invariant chain peptide than non-RA-associated HLA-DR alleles. J. Immunol. 167, 7157–7168 (2001).

    Article  CAS  Google Scholar 

  41. Reed, A.M., Collins, E.J., Shock, L.P., Klapper, D.G. & Frelinger, J.A. Diminished class II-associated Ii peptide binding to the juvenile dermatomyositis HLA-DQ α1*0501/DQ β1*0301 molecule. J. Immunol. 159, 6260–6265 (1997).

    CAS  Google Scholar 

  42. Hu, R., Beck, C., Chang, Y.B. & DeGroot, L.J. HLA class II genes in Graves' disease. Autoimmunity 12, 103–106 (1992).

    Article  CAS  Google Scholar 

  43. Strettell, M.D. et al. Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis. Gastroenterology 112, 2028–2035 (1997).

    Article  CAS  Google Scholar 

  44. Hausmann, D.H., Yu, B., Hausmann, S. & Wucherpfennig, K.W. pH-dependent peptide binding properties of the type I diabetes-associated I-Ag7 molecule: rapid release of CLIP at an endosomal pH. J. Exp. Med. 189, 1723–1734 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Chicz, R.M. et al. Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J. Exp. Med. 178, 27–47 (1993).

    Article  CAS  Google Scholar 

  46. Smith, M.H. et al. Baculoviral expressed HLA class I heavy chains used to screen a synthetic peptide library for allele-specific peptide binding motifs. Mol. Immunol. 35, 1033–1043 (1998).

    Article  CAS  Google Scholar 

  47. Sallusto, F. & Lanzavecchia, A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J. Exp. Med. 179, 1109–1118 (1994).

    Article  CAS  Google Scholar 

  48. Kropshofer, H., Vogt, A.B., Stern, L.J. & Hammerling, G.J. Self-release of CLIP in peptide loading of HLA-DR molecules. Science 270, 1357–1359 (1995).

    Article  CAS  Google Scholar 

  49. Washburn, M.P., Wolters, D. & Yates, J.R. 3rd. Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat. Biotechnol. 19, 242–247 (2001).

    Article  CAS  Google Scholar 

  50. Wolters, D.A., Washburn, M.P. & Yates, J.R. 3rd. An automated multidimensional protein identification technology for shotgun proteomics. Anal. Chem. 73, 5683–5690 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Lallouet and N. Platania for expert technical assistance; B. Bohrmann and K. Oroszlan-Szovik (Roche Pharmaceuticals, Basel, Switzerland) for help with confocal microscopy; D. Nguyen and H. Klueter (Instituto for Transfusionmedicine and Immunology, Mannheim, Germany) for HLA-typed blood samples; and C. Benoist, D. Mathis and R. Obst (Harvard Medical School, Boston, Massachusetts) for providing H2-DM-deficient mice. The Basel Institute was founded and supported by F. Hoffmann-La Roche (Basel, Switzerland).

Author information

Author notes

  1. Marianne Boes

    Present address: Department of Dermatology, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts, USA

  2. Dirk Wolters

    Present address: Department of Analytical Chemistry, Biomolecular Mass-Spectrometry, University of Bochum, Germany

Authors and Affiliations

  1. Basel Institute for Immunology, Basel, Switzerland

    Till A Röhn, Sebastian Spindeldreher, Anne B Vogt & Harald Kropshofer

  2. F. Hoffmann-La Roche AG, Pharmaceutical Research, Basel, Switzerland

    Till A Röhn, Dirk Wolters, Sebastian Spindeldreher, Bernd Müller, Hanno Langen, Anne B Vogt & Harald Kropshofer

  3. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Marianne Boes & Hidde Ploegh

Authors
  1. Till A Röhn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marianne Boes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dirk Wolters
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sebastian Spindeldreher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bernd Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hanno Langen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hidde Ploegh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anne B Vogt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Harald Kropshofer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Harald Kropshofer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

CLIP is a constituent of synapses formed between DCs and autologous T cells. (PDF 1529 kb)

Supplementary Fig. 2

Exogenous IL-12 reverts the antagonistic effect of CLIP on TH1 polarization. (PDF 48 kb)

Supplementary Fig. 3

Specificity of polycloncal rabbit IgG α-CLIP. (PDF 171 kb)

Supplementary Fig. 4

Capacity to load HLA-DR with exogenous antigen upon maturation. (PDF 97 kb)

Supplementary Table 1

HLA-DR (DRB*0101/1201) associated self-peptides of DCs (PDF 75 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Röhn, T., Boes, M., Wolters, D. et al. Upregulation of the CLIP self peptide on mature dendritic cells antagonizes T helper type 1 polarization. Nat Immunol 5, 909–918 (2004). https://doi.org/10.1038/ni1108

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1108

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing