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Inhibitory Role of IFN--Inducible Lysosomal Thiol Reductase in T Cell Activation¹

Igor Barjaktarevi^*, Ayman Rahman, Sasa Radoja^*, Branka Bogunovi, Alison Vollmer^*, Stanislav Vukmanovi^* and Maja Mari^2,

^* Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Washington, DC 20010; and Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057

IFN--inducible lysosomal thiol reductase (GILT) is a unique thiol reductase with optimal enzymatic activity at low pH. GILT plays a crucial role in unfolding the antigenic proteins in preparation for their proteolytic cleavage and presentation of resulting peptides by MHC class II. In this study, we demonstrate that GILT is expressed in T lymphocytes and that it has an APC-nonrelated role in the regulation of T cell activation. Surprisingly, comparison of wild-type and GILT-deficient T cell activation in vitro revealed stronger responsiveness in the absence of GILT. The effect of GILT in reducing the proliferative and cytotoxic responses was endogenous to T cells and resulted from decreased sensitivity at the individual cell level. Therefore, a molecule with primarily lysosomal localization suppresses T cell activation, a process characterized by signal transmission from plasma membrane to cytoplasm and nucleus.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by American Cancer Society Grant RSG-05-204-01-LIB (to M.M.) and National Institutes of Health Grants AI48837 and AI41573 (to S.V.).

² Address correspondence and reprint requests to Maja Mari, Department of Microbiology and Immunology, Georgetown University Medical Center, 3900 Reservoire Road NW, Med/Dent C301, Washington, DC 20057. E-mail address: mam254{at}georgetown.edu

³ Abbreviations used in this paper: GILT, IFN--inducible lysosomal thiol reductase; WT, wild type; KO, knockout; ROS, reactive oxygen species.

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