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Down-Modulation of CXCR3 Surface Expression and Function in CD8⁺ T Cells from Cutaneous T Cell Lymphoma Patients¹

Dorian Winter^*,, Julia Moser, Ernst Kriehuber^*,, Christoph Wiesner, Robert Knobler, Franz Trautinger, Paula Bombosi^¶, Georg Stingl, Peter Petzelbauer, Antal Rot^¶ and Dieter Maurer^2,*

^* Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria; Division of Immunology, Allergy, and Infectious Diseases, Division of Special and Environmental Dermatology, and Division of General Dermatology, Department of Dermatology, Medical University of Vienna, Vienna, Austria; and ^¶ Novartis Institutes for Biomedical Research, Vienna, Austria

Viruses can escape destruction by the immune system by exploitation of the chemokine-chemokine receptor system. It is less established whether human cancers can adopt similar strategies to evade immunologic control. In this study, we show that advanced cutaneous T cell lymphoma (CTCL) is associated with selective and efficient inactivation of CXCR3-dependent T cell migration. Our studies demonstrate that this alteration is at least in part due to CXCR3 down-regulation in vivo by elevated serum levels of CXCR3 ligands. The T cell population most affected by this down-regulatory mechanism are CD8⁺ cytotoxic effector T cells. In CTCL patients, cytotoxic effector T cells have strongly reduced surface CXCR3 expression, accumulate in peripheral blood, but are virtually absent from CTCL tumor lesions, indicating an inability to extravasate into lymphoma tissue. CTCL-associated inactivation of effector cell recruitment may be a paradigmatic example of a new type of immune escape mechanisms shielding the neoplasm from a tumoricidal attack.

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 Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, the Austrian Science Foundation (Fonds zur Forderung der Wissenschaftlichen Forschung; Projects SFB F1813 and SFB F2308), and the Genome Research in Austria (GEN-AU) program of the Austrian Ministry of Science (to D.M.).

² Address correspondence and reprint requests to Dr. Dieter Maurer, Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail address: dieter.maurer{at}meduniwien.ac.at

³ Abbreviations used in this paper: CTCL, cutaneous T cell lymphoma; 7-AAD, 7-aminoactinomycin D; ₂m, ₂-microglobulin; CXCR3L, CXCR3 ligand; EEA, early endosomal Ag; ECP, extracorporeal photochemotherapy; LAMP, lysosome-associated membrane protein; PB, peripheral blood; VZV, varicella zoster virus.

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The JI 2007 179: 3389-3390. [Full Text]