Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Jun 1;101(11):2351–2363. doi: 10.1172/JCI1158

Cathepsin S activity regulates antigen presentation and immunity.

R J Riese 1, R N Mitchell 1, J A Villadangos 1, G P Shi 1, J T Palmer 1, E R Karp 1, G T De Sanctis 1, H L Ploegh 1, H A Chapman 1
PMCID: PMC508824  PMID: 9616206

Abstract

MHC class II molecules display antigenic peptides on cell surfaces for recognition by CD4(+) T cells. Proteolysis is required in this process both for degradation of invariant chain (Ii) from class II-Ii complexes to allow subsequent binding of peptides, and for generation of the antigenic peptides. The cysteine endoprotease, cathepsin S, mediates Ii degradation in human and mouse antigen-presenting cells. Studies described here examine the functional significance of cathepsin S inhibition on antigen presentation and immunity. Specific inhibition of cathepsin S in A20 cells markedly impaired presentation of an ovalbumin epitope by interfering with class II-peptide binding, not by obstructing generation of the antigen. Administration of a cathepsin S inhibitor to mice in vivo selectively inhibited activity of cathepsin S in splenocytes, resulting in accumulation of a class II-associated Ii breakdown product, attenuation of class II-peptide complex formation, and inhibition of antigen presentation. Mice treated with inhibitor had an attenuated antibody response when immunized with ovalbumin but not the T cell-independent antigen TNP-Ficoll. In a mouse model of pulmonary hypersensitivity, treatment with the inhibitor also abrogated a rise in IgE titers and profoundly blocked eosinophilic infiltration in the lung. Thus, inhibition of cathepsin S in vivo alters Ii processing, antigen presentation, and immunity. These data identify selective inhibition of cysteine proteases as a potential therapeutic strategy for asthma and autoimmune disease processes.

Full Text

The Full Text of this article is available as a PDF (436.1 KB).

Selected References

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

  1. Amigorena S., Drake J. R., Webster P., Mellman I. Transient accumulation of new class II MHC molecules in a novel endocytic compartment in B lymphocytes. Nature. 1994 May 12;369(6476):113–120. doi: 10.1038/369113a0. [DOI] [PubMed] [Google Scholar]
  2. Barnes K. A., Mitchell R. N. Detection of functional class II-associated antigen: role of a low density endosomal compartment in antigen processing. J Exp Med. 1995 May 1;181(5):1715–1727. doi: 10.1084/jem.181.5.1715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beasley R., Roche W. R., Roberts J. A., Holgate S. T. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis. 1989 Mar;139(3):806–817. doi: 10.1164/ajrccm/139.3.806. [DOI] [PubMed] [Google Scholar]
  4. Bevec T., Stoka V., Pungercic G., Dolenc I., Turk V. Major histocompatibility complex class II-associated p41 invariant chain fragment is a strong inhibitor of lysosomal cathepsin L. J Exp Med. 1996 Apr 1;183(4):1331–1338. doi: 10.1084/jem.183.4.1331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bijlmakers M. J., Benaroch P., Ploegh H. L. Mapping functional regions in the lumenal domain of the class II-associated invariant chain. J Exp Med. 1994 Aug 1;180(2):623–629. doi: 10.1084/jem.180.2.623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Bozic C. R., Kolakowski L. F., Jr, Gerard N. P., Garcia-Rodriguez C., von Uexkull-Guldenband C., Conklyn M. J., Breslow R., Showell H. J., Gerard C. Expression and biologic characterization of the murine chemokine KC. J Immunol. 1995 Jun 1;154(11):6048–6057. [PubMed] [Google Scholar]
  8. Brachet V., Raposo G., Amigorena S., Mellman I. Ii chain controls the transport of major histocompatibility complex class II molecules to and from lysosomes. J Cell Biol. 1997 Apr 7;137(1):51–65. doi: 10.1083/jcb.137.1.51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Buus S., Colon S., Smith C., Freed J. H., Miles C., Grey H. M. Interaction between a "processed" ovalbumin peptide and Ia molecules. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3968–3971. doi: 10.1073/pnas.83.11.3968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chicz R. M., Urban R. G., Lane W. S., Gorga J. C., Stern L. J., Vignali D. A., Strominger J. L. Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size. Nature. 1992 Aug 27;358(6389):764–768. doi: 10.1038/358764a0. [DOI] [PubMed] [Google Scholar]
  11. Cresswell P. Antigen presentation. Getting peptides into MHC class II molecules. Curr Biol. 1994 Jun 1;4(6):541–543. doi: 10.1016/s0960-9822(00)00119-6. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Denzin L. K., Hammond C., Cresswell P. HLA-DM interactions with intermediates in HLA-DR maturation and a role for HLA-DM in stabilizing empty HLA-DR molecules. J Exp Med. 1996 Dec 1;184(6):2153–2165. doi: 10.1084/jem.184.6.2153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Diment S. Different roles for thiol and aspartyl proteases in antigen presentation of ovalbumin. J Immunol. 1990 Jul 15;145(2):417–422. [PubMed] [Google Scholar]
  15. Fineschi B., Sakaguchi K., Appella E., Miller J. The proteolytic environment involved in MHC class II-restricted antigen presentation can be modulated by the p41 form of invariant chain. J Immunol. 1996 Oct 15;157(8):3211–3215. [PubMed] [Google Scholar]
  16. Frevert C. W., Huang S., Danaee H., Paulauskis J. D., Kobzik L. Functional characterization of the rat chemokine KC and its importance in neutrophil recruitment in a rat model of pulmonary inflammation. J Immunol. 1995 Jan 1;154(1):335–344. [PubMed] [Google Scholar]
  17. Gajewski T. F., Pinnas M., Wong T., Fitch F. W. Murine Th1 and Th2 clones proliferate optimally in response to distinct antigen-presenting cell populations. J Immunol. 1991 Mar 15;146(6):1750–1758. [PubMed] [Google Scholar]
  18. Germain R. N. MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell. 1994 Jan 28;76(2):287–299. doi: 10.1016/0092-8674(94)90336-0. [DOI] [PubMed] [Google Scholar]
  19. Ghosh P., Amaya M., Mellins E., Wiley D. C. The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3. Nature. 1995 Nov 30;378(6556):457–462. doi: 10.1038/378457a0. [DOI] [PubMed] [Google Scholar]
  20. Griffith I. J., Nabavi N., Ghogawala Z., Chase C. G., Rodriguez M., McKean D. J., Glimcher L. H. Structural mutation affecting intracellular transport and cell surface expression of murine class II molecules. J Exp Med. 1988 Feb 1;167(2):541–555. doi: 10.1084/jem.167.2.541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Griscelli C., Lisowska-Grospierre B., Mach B. Combined immunodeficiency with defective expression in MHC class II genes. Immunodefic Rev. 1989;1(2):135–153. [PubMed] [Google Scholar]
  22. Grusby M. J., Auchincloss H., Jr, Lee R., Johnson R. S., Spencer J. P., Zijlstra M., Jaenisch R., Papaioannou V. E., Glimcher L. H. Mice lacking major histocompatibility complex class I and class II molecules. Proc Natl Acad Sci U S A. 1993 May 1;90(9):3913–3917. doi: 10.1073/pnas.90.9.3913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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. 1995 Nov 1;182(5):1579–1584. doi: 10.1084/jem.182.5.1579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Karasuyama H., Melchers F. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. Eur J Immunol. 1988 Jan;18(1):97–104. doi: 10.1002/eji.1830180115. [DOI] [PubMed] [Google Scholar]
  25. Krinzman S. J., De Sanctis G. T., Cernadas M., Mark D., Wang Y., Listman J., Kobzik L., Donovan C., Nassr K., Katona I. Inhibition of T cell costimulation abrogates airway hyperresponsiveness in a murine model. J Clin Invest. 1996 Dec 15;98(12):2693–2699. doi: 10.1172/JCI119093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kung T. T., Jones H., Adams G. K., 3rd, Umland S. P., Kreutner W., Egan R. W., Chapman R. W., Watnick A. S. Characterization of a murine model of allergic pulmonary inflammation. Int Arch Allergy Immunol. 1994 Sep;105(1):83–90. doi: 10.1159/000236807. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Linsley P. S., Wallace P. M., Johnson J., Gibson M. G., Greene J. L., Ledbetter J. A., Singh C., Tepper M. A. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science. 1992 Aug 7;257(5071):792–795. doi: 10.1126/science.1496399. [DOI] [PubMed] [Google Scholar]
  29. Mason R. W., Wilcox D., Wikstrom P., Shaw E. N. The identification of active forms of cysteine proteinases in Kirsten-virus-transformed mouse fibroblasts by use of a specific radiolabelled inhibitor. Biochem J. 1989 Jan 1;257(1):125–129. doi: 10.1042/bj2570125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Matsunaga Y., Saibara T., Kido H., Katunuma N. Participation of cathepsin B in processing of antigen presentation to MHC class II. FEBS Lett. 1993 Jun 21;324(3):325–330. doi: 10.1016/0014-5793(93)80144-j. [DOI] [PubMed] [Google Scholar]
  31. Metlay J. P., Witmer-Pack M. D., Agger R., Crowley M. T., Lawless D., Steinman R. M. The distinct leukocyte integrins of mouse spleen dendritic cells as identified with new hamster monoclonal antibodies. J Exp Med. 1990 May 1;171(5):1753–1771. doi: 10.1084/jem.171.5.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mudde G. C., Reischul I. G., Corvaïa N., Hren A., Poellabauer E. M. Antigen presentation in allergic sensitization. Immunol Cell Biol. 1996 Apr;74(2):167–173. doi: 10.1038/icb.1996.23. [DOI] [PubMed] [Google Scholar]
  33. Neefjes J. J., Ploegh H. L. Inhibition of endosomal proteolytic activity by leupeptin blocks surface expression of MHC class II molecules and their conversion to SDS resistance alpha beta heterodimers in endosomes. EMBO J. 1992 Feb;11(2):411–416. doi: 10.1002/j.1460-2075.1992.tb05069.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Newcomb J. R., Cresswell P. Structural analysis of proteolytic products of MHC class II-invariant chain complexes generated in vivo. J Immunol. 1993 Oct 15;151(8):4153–4163. [PubMed] [Google Scholar]
  35. Nguyen Q. V., Knapp W., Humphreys R. E. Inhibition by leupeptin and antipain of the intracellular proteolysis of Ii. Hum Immunol. 1989 Mar;24(3):153–163. doi: 10.1016/0198-8859(89)90056-6. [DOI] [PubMed] [Google Scholar]
  36. Ohkawara Y., Lei X. F., Stämpfli M. R., Marshall J. S., Xing Z., Jordana M. Cytokine and eosinophil responses in the lung, peripheral blood, and bone marrow compartments in a murine model of allergen-induced airways inflammation. Am J Respir Cell Mol Biol. 1997 May;16(5):510–520. doi: 10.1165/ajrcmb.16.5.9160833. [DOI] [PubMed] [Google Scholar]
  37. Palmer J. T., Rasnick D., Klaus J. L., Brömme D. Vinyl sulfones as mechanism-based cysteine protease inhibitors. J Med Chem. 1995 Aug 18;38(17):3193–3196. doi: 10.1021/jm00017a002. [DOI] [PubMed] [Google Scholar]
  38. Pfeiffer C., Stein J., Southwood S., Ketelaar H., Sette A., Bottomly K. Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo. J Exp Med. 1995 Apr 1;181(4):1569–1574. doi: 10.1084/jem.181.4.1569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Reyes V. E., Lu S., Humphreys R. E. Cathepsin B cleavage of Ii from class II MHC alpha- and beta-chains. J Immunol. 1991 Jun 1;146(11):3877–3880. [PubMed] [Google Scholar]
  40. 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]
  41. Riese R. J., Wolf P. R., Brömme D., Natkin L. R., Villadangos J. A., Ploegh H. L., Chapman H. A. Essential role for cathepsin S in MHC class II-associated invariant chain processing and peptide loading. Immunity. 1996 Apr;4(4):357–366. doi: 10.1016/s1074-7613(00)80249-6. [DOI] [PubMed] [Google Scholar]
  42. 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]
  43. Roche P. A., Marks M. S., Cresswell P. Formation of a nine-subunit complex by HLA class II glycoproteins and the invariant chain. Nature. 1991 Dec 5;354(6352):392–394. doi: 10.1038/354392a0. [DOI] [PubMed] [Google Scholar]
  44. Rodriguez G. M., Diment S. Role of cathepsin D in antigen presentation of ovalbumin. J Immunol. 1992 Nov 1;149(9):2894–2898. [PubMed] [Google Scholar]
  45. 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]
  46. Shachar I., Flavell R. A. Requirement for invariant chain in B cell maturation and function. Science. 1996 Oct 4;274(5284):106–108. doi: 10.1126/science.274.5284.106. [DOI] [PubMed] [Google Scholar]
  47. Shaw A. C., Mitchell R. N., Weaver Y. K., Campos-Torres J., Abbas A. K., Leder P. Mutations of immunoglobulin transmembrane and cytoplasmic domains: effects on intracellular signaling and antigen presentation. Cell. 1990 Oct 19;63(2):381–392. doi: 10.1016/0092-8674(90)90171-a. [DOI] [PubMed] [Google Scholar]
  48. 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]
  49. Shi G. P., Webb A. C., Foster K. E., Knoll J. H., Lemere C. A., Munger J. S., Chapman H. A. Human cathepsin S: chromosomal localization, gene structure, and tissue distribution. J Biol Chem. 1994 Apr 15;269(15):11530–11536. [PubMed] [Google Scholar]
  50. 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]
  51. Tulp A., Verwoerd D., Dobberstein B., Ploegh H. L., Pieters J. Isolation and characterization of the intracellular MHC class II compartment. Nature. 1994 May 12;369(6476):120–126. doi: 10.1038/369120a0. [DOI] [PubMed] [Google Scholar]
  52. Venge P., Håkansson L. Current understanding of the role of the eosinophil granulocyte in asthma. Clin Exp Allergy. 1991 May;21 (Suppl 3):31–37. doi: 10.1111/j.1365-2222.1991.tb01761.x. [DOI] [PubMed] [Google Scholar]
  53. Villadangos J. A., Riese R. J., Peters C., Chapman H. A., Ploegh H. L. Degradation of mouse invariant chain: roles of cathepsins S and D and the influence of major histocompatibility complex polymorphism. J Exp Med. 1997 Aug 18;186(4):549–560. doi: 10.1084/jem.186.4.549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. 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]
  55. West M. A., Lucocq J. M., Watts C. Antigen processing and class II MHC peptide-loading compartments in human B-lymphoblastoid cells. Nature. 1994 May 12;369(6476):147–151. doi: 10.1038/369147a0. [DOI] [PubMed] [Google Scholar]
  56. White J., Blackman M., Bill J., Kappler J., Marrack P., Gold D. P., Born W. Two better cell lines for making hybridomas expressing specific T cell receptors. J Immunol. 1989 Sep 15;143(6):1822–1825. [PubMed] [Google Scholar]
  57. 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]
  58. van Noort J. M., van der Drift A. C. The selectivity of cathepsin D suggests an involvement of the enzyme in the generation of T-cell epitopes. J Biol Chem. 1989 Aug 25;264(24):14159–14164. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES