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Cutting Edge: Developmental Up-Regulation of IFN--Inducible Lysosomal Thiol Reductase Expression Leads to Reduced T Cell Sensitivity and Less Severe Autoimmunity¹

Maja Maric^2,*, Igor Barjaktarevic^3,, Branka Bogunovic^*, Milica Stojakovic, Christine Maric^4, and Stanislav Vukmanovic

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

Reactivity to self-peptide/MHC complexes is required for selection of the TCR repertoire in the thymus but can also promote autoimmunity. Reduced TCR sensitivity of mature T cells is thought to help control the autoreactivity in peripheral T cells. The molecular basis for reduced sensitivity of peripheral T cells is not known. We found that peripheral T cells, but not immature thymocytes, lacking IFN--inducible lysosomal thiol reductase (GILT) display increased sensitivity to TCR ligation. GILT^–/– peripheral T cells express reduced levels of mitochondrial superoxide dismutase 2 and consequently display higher levels of reactive oxygen radicals and ERK1/2 phosphorylation following activation. The increased sensitivity of GILT-deficient T cells results in a more severe hyperglycemia associated with streptozotocin-induced diabetes. GILT expression levels progressively increase in T cells with maturation. These data suggest that regulation of GILT expression may be a mechanism of T cell differentiation-associated changes in sensitivity to TCR engagement.

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 the American Cancer Society Grant 109234RSG and American Heart Association Scientist Development Grant 0535032N (to M.M.), the Iacocca Foundation, and National Institutes of Health Grants AI48837 and AI41573 (to S.V.).

² Address correspondence and reprint requests to Dr. Maja Maric, Department of Microbiology and Immunology, Georgetown University School of Medicine, Washington, DC 20057. E-mail address: mam254{at}georgetown.edu

³ Current address: Department of Medicine, New York University Langone Medical Center, 530 First Avenue, New York, NY 10016.

⁴ Current address: Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson MS 39216.

⁵ Abbreviations used in this paper: GILT, IFN- inducible lysosomal thiol reductase; BTLA, B and T cell lymphocyte attenuator; SOD, superoxide dismutase; STZ, streptozotocin; WT, wild type.