Cathepsin S activity regulates antigen presentation and immunity.
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.
Riese
R J
RJ
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Mitchell
R N
RN
Villadangos
J A
JA
Shi
G P
GP
Palmer
J T
JT
Karp
E R
ER
De Sanctis
G T
GT
Ploegh
H L
HL
Chapman
H A
HA
D000818:Animals; D017951:Antigen Presentation; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002460:Cell Line; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007109:Immunity; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; C045084:invariant chain; D010047:Ovalbumin; D002403:Cathepsins; C028217:cathepsin S