The Journal of Experimental Medicine
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Published online 13 May 2002 doi:10.1084/jem.20011853
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© Rockefeller University Press, 0022-1007/2002/5/1267/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 10, May 20, 2002 1267-1277

Absence of {gamma}-Interferon–inducible Lysosomal Thiol Reductase in Melanomas Disrupts T Cell Recognition of Select Immunodominant Epitopes

M. Azizul Haque1,3, Ping Li1,3, Sheila K. Jackson1,3, Hassane M. Zarour4, John W. Hawes2, Uyen T. Phan5, Maja Maric5, Peter Cresswell5 and Janice S. Blum1,3

1 Department of Microbiology and Immunology, Indiana University School of Medicine
2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine
3 Walther Oncology Center, Walther Cancer Institute, Indianapolis, IN 46202
4 Department of Medicine and Melanoma Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
5 Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520

Address correspondence to Janice S. Blum, Department of Microbiology and Immunology, and the Walther Oncology Center, Indiana University School of Medicine, and the Walther Cancer Institute, Indianapolis, IN 46202. Phone: 317-278-1715; Fax: 317-274-4090; E-mail: jblum{at}iupui.edu

Long-lasting tumor immunity requires functional mobilization of CD8+ and CD4+ T lymphocytes. CD4+ T cell activation is enhanced by presentation of shed tumor antigens by professional antigen-presenting cells (APCs), coupled with display of similar antigenic epitopes by major histocompatibility complex class II on malignant cells. APCs readily processed and presented several self-antigens, yet T cell responses to these proteins were absent or reduced in the context of class II+ melanomas. T cell recognition of select exogenous and endogenous epitopes was dependent on tumor cell expression of {gamma}-interferon–inducible lysosomal thiol reductase (GILT). The absence of GILT in melanomas altered antigen processing and the hierarchy of immunodominant epitope presentation. Mass spectral analysis also revealed GILT's ability to reduce cysteinylated epitopes. Such disparities in the profile of antigenic epitopes displayed by tumors and bystander APCs may contribute to tumor cell survival in the face of immunological defenses.

Key Words: MHC class II molecules • melanomas • cysteinylation • GILT • immunodominance


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