Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 9 November 2001:
Vol. 294. no. 5545, pp. 1361 - 1365
DOI: 10.1126/science.1065500
Prev | Table of Contents

Reports

Defective Antigen Processing in GILT-Free Mice

Maja Maric,1 Balasubramanian Arunachalam,1* Uyen T. Phan,1 Chen Dong,1dagger Wendy S. Garrett,1 Kurt S. Cannon,1 Christopher Alfonso,2ddagger Lars Karlsson,2 Richard A. Flavell,1 Peter Cresswell1§

Processing of proteins for major histocompatibility complex (MHC) class II-restricted presentation to CD4-positive T lymphocytes occurs after they are internalized by antigen-presenting cells (APCs). Antigenic proteins frequently contain disulfide bonds, and their reduction in the endocytic pathway facilitates processing. In humans, a gamma interferon-inducible lysosomal thiol reductase (GILT) is constitutively present in late endocytic compartments of APCs. Here, we identified the mouse homolog of GILT and generated a GILT knockout mouse. GILT facilitated the processing and presentation to antigen-specific T cells of protein antigens containing disulfide bonds. The response to hen egg lysozyme, a model antigen with a compact structure containing four disulfide bonds, was examined in detail.

1 Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
2 R. W. Johnson Pharmaceutical Research Institute, 3210 Merryfield Row, San Diego, CA 92121, USA.
*   Present address: Aventis Pasteur, Discovery Drive, Route 611, Swiftwater, PA 18370, USA.

dagger    Present address: Department of Immunology, University of Washington, 1959 N.E. Pacific Street, Seattle, WA 98195, USA.

ddagger    Present address: Department of Immunology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

§   To whom correspondence should be addressed. E-mail: peter.cresswell{at}yale.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Expression of survivin in lung eosinophils is associated with pathology in a mouse model of allergic asthma.
D. J. Tumes, A. Connolly, and L. A. Dent (2009)
Int. Immunol. 21, 633-644
   Abstract »    Full Text »    PDF »
Cutting Edge: Developmental Up-Regulation of IFN-{gamma}-Inducible Lysosomal Thiol Reductase Expression Leads to Reduced T Cell Sensitivity and Less Severe Autoimmunity.
M. Maric, I. Barjaktarevic, B. Bogunovic, M. Stojakovic, C. Maric, and S. Vukmanovic (2009)
J. Immunol. 182, 746-750
   Abstract »    Full Text »    PDF »
B Cells Induce Tolerance by Presenting Endogenous Peptide-IgG on MHC Class II Molecules via an IFN-{gamma}-Inducible Lysosomal Thiol Reductase-Dependent Pathway.
Y. Su, G. Carey, M. Maric, and D. W. Scott (2008)
J. Immunol. 181, 1153-1160
   Abstract »    Full Text »    PDF »
Modulation of the immune responses in chickens by low-pathogenicity avian influenza virus H9N2.
Z. Xing, C. J. Cardona, J. Li, N. Dao, T. Tran, and J. Andrada (2008)
J. Gen. Virol. 89, 1288-1299
   Abstract »    Full Text »    PDF »
An Unexpected Functional Link between Lysosomal Thiol Reductase and Mitochondrial Manganese Superoxide Dismutase.
B. Bogunovic, M. Stojakovic, L. Chen, and M. Maric (2008)
J. Biol. Chem. 283, 8855-8862
   Abstract »    Full Text »    PDF »
Target Peptide Sequence within Infectious Human Immunodeficiency Virus Type 1 Does Not Ensure Envelope-Specific T-Helper Cell Reactivation: Influences of Cysteine Protease and Gamma Interferon-Induced Thiol Reductase Activities.
R. Sealy, W. Chaka, S. Surman, S. A. Brown, P. Cresswell, and J. L. Hurwitz (2008)
Clin. Vaccine Immunol. 15, 713-719
   Abstract »    Full Text »    PDF »
Functional Requirements for the Lysosomal Thiol Reductase GILT in MHC Class II-Restricted Antigen Processing.
K. T. Hastings, R. L. Lackman, and P. Cresswell (2006)
J. Immunol. 177, 8569-8577
   Abstract »    Full Text »    PDF »
Inhibitory Role of IFN-{gamma}-Inducible Lysosomal Thiol Reductase in T Cell Activation.
I. Barjaktarevic, A. Rahman, S. Radoja, B. Bogunovic, A. Vollmer, S. Vukmanovic, and M. Maric (2006)
J. Immunol. 177, 4369-4375
   Abstract »    Full Text »    PDF »
Oxidizing potential of endosomes and lysosomes limits intracellular cleavage of disulfide-based antibody-drug conjugates.
C. D. Austin, X. Wen, L. Gazzard, C. Nelson, R. H. Scheller, and S. J. Scales (2005)
PNAS 102, 17987-17992
   Abstract »    Full Text »    PDF »
Cross-Reactive Cytotoxic T Lymphocytes against Human Immunodeficiency Virus Type 1 Protease and Gamma Interferon-Inducible Protein 30.
R. D. Mason, M. I. Bowmer, C. M. Howley, and M. D. Grant (2005)
J. Virol. 79, 5529-5536
   Abstract »    Full Text »    PDF »
Genes "Waiting" for Recruitment by the Adaptive Immune System: The Insights from Amphioxus.
C. Yu, M. Dong, X. Wu, S. Li, S. Huang, J. Su, J. Wei, Y. Shen, C. Mou, X. Xie, et al. (2005)
J. Immunol. 174, 3493-3500
   Abstract »    Full Text »    PDF »
Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response.
S. Monti, K. J. Savage, J. L. Kutok, F. Feuerhake, P. Kurtin, M. Mihm, B. Wu, L. Pasqualucci, D. Neuberg, R. C. T. Aguiar, et al. (2005)
Blood 105, 1851-1861
   Abstract »    Full Text »    PDF »
Antigen Stability Controls Antigen Presentation.
R. Thai, G. Moine, M. Desmadril, D. Servent, J.-L. Tarride, A. Menez, and M. Leonetti (2004)
J. Biol. Chem. 279, 50257-50266
   Abstract »    Full Text »    PDF »
Vesicle Size Influences the Trafficking, Processing, and Presentation of Antigens in Lipid Vesicles.
J. M. Brewer, K. G. J. Pollock, L. Tetley, and D. G. Russell (2004)
J. Immunol. 173, 6143-6150
   Abstract »    Full Text »    PDF »
Isolation and Characterization of an Arabidopsis Mutant That Overaccumulates O-Acetyl-L-Ser.
N. Ohkama-Ohtsu, I. Kasajima, T. Fujiwara, and S. Naito (2004)
Plant Physiology 136, 3209-3222
   Abstract »    Full Text »    PDF »
Cutting Edge: Induction of the Antigen-Processing Enzyme IFN-{gamma}-Inducible Lysosomal Thiol Reductase in Melanoma Cells Is STAT1-Dependent but CIITA-Independent.
P. W. O'Donnell, A. Haque, M. J. Klemsz, M. H. Kaplan, and J. S. Blum (2004)
J. Immunol. 173, 731-735
   Abstract »    Full Text »    PDF »
Differential Requirements for Endosomal Reduction in the Presentation of Two H2-Ed-Restricted Epitopes from Influenza Hemagglutinin.
G. Sinnathamby, M. Maric, P. Cresswell, and L. C. Eisenlohr (2004)
J. Immunol. 172, 6607-6614
   Abstract »    Full Text »    PDF »
Differential Processing of CD4 T-cell Epitopes from the Protective Antigen of Bacillus anthracis.
J. A. Musson, N. Walker, H. Flick-Smith, E. D. Williamson, and J. H. Robinson (2003)
J. Biol. Chem. 278, 52425-52431
   Abstract »    Full Text »    PDF »
Developmental markers of B cells are superior to those of T cells for identification of stages with distinct gene expression profiles.
R. Hoffmann, T. Seidl, L. Bruno, and M. Dugas (2003)
J. Leukoc. Biol. 74, 602-610
   Abstract »    Full Text »    PDF »
Molecular Interaction and Enzymatic Activity of Macrophage Migration Inhibitory Factor with Immunorelevant Peptides.
I. Potolicchio, L. Santambrogio, and J. L. Strominger (2003)
J. Biol. Chem. 278, 30889-30895
   Abstract »    Full Text »    PDF »
Redirection of B cell responsiveness by transforming growth factor {beta} receptor.
J. Roes, B. K. Choi, and B. B. Cazac (2003)
PNAS 100, 7241-7246
   Abstract »    Full Text »    PDF »
Role of the C-terminal propeptide in the activity and maturation of gamma -interferon-inducible lysosomal thiol reductase (GILT).
U. T. Phan, R. L. Lackman, and P. Cresswell (2002)
PNAS 99, 12298-12303
   Abstract »    Full Text »    PDF »
Role of Disulfide Bonds in Regulating Antigen Processing and Epitope Selection.
P. Li, M. A. Haque, and J. S. Blum (2002)
J. Immunol. 169, 2444-2450
   Abstract »    Full Text »    PDF »
Analysis of Protease Activity in Live Antigen-presenting Cells Shows Regulation of the Phagosomal Proteolytic Contents During Dendritic Cell Activation.
A.-M. Lennon-Dumenil, A. H. Bakker, R. Maehr, E. Fiebiger, H. S. Overkleeft, M. Rosemblatt, H. L. Ploegh, and C. Lagaudriere-Gesbert (2002)
J. Exp. Med. 196, 529-540
   Abstract »    Full Text »    PDF »
Distinct recognition by two subsets of T cells of an MHC class II-peptide complex.
Z. Pu, J. A. Carrero, and E. R. Unanue (2002)
PNAS 99, 8844-8849
   Abstract »    Full Text »    PDF »
Absence of {gamma}-Interferon-inducible Lysosomal Thiol Reductase in Melanomas Disrupts T Cell Recognition of Select Immunodominant Epitopes.
M. A. Haque, P. Li, S. K. Jackson, H. M. Zarour, J. W. Hawes, U. T. Phan, M. Maric, P. Cresswell, and J. S. Blum (2002)
J. Exp. Med. 195, 1267-1277
   Abstract »    Full Text »    PDF »
Efficient Delivery of T Cell Epitopes to APC by Use of MHC Class II-Specific Troybodies.
E. Lunde, K. H. Western, I. B. Rasmussen, I. Sandlie, and B. Bogen (2002)
J. Immunol. 168, 2154-2162
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)