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Tumor-Induced Impairment of TCR Signaling Results in Compromised Functionality of Tumor-Infiltrating Regulatory T Cells¹

M. E. Christine Lutsiak^*, Yutaka Tagaya, Anthony J. Adams, Jeffrey Schlom^2,* and Helen Sabzevari^*

^* Laboratory of Tumor Immunology and Biology, Metabolism Branch, and Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

This study demonstrates, for the first time, that murine regulatory T (Treg) cells in the tumor microenvironment display both enhanced proliferation and reduced functionality. This enhanced proliferation, combined with decreased apoptosis, leads to an intratumoral accumulation of Treg cells with a unique phenotype: CD4⁺CD25⁺FoxP3⁺GITR^highCD27^lowCD62L^–. The loss of functionality is associated with down-regulation of the TCR signaling complex, including IL-2-inducible T cell kinase. It is also demonstrated that tumor-infiltrating Treg cells have impaired TCR-mediated signaling and calcium influx. Based on these findings, this study supports the hypothesis that 1) tumor-infiltrating Treg cells lose functionality due to their diminished ability to become effectively activated and 2) intratumoral accumulation of Treg cells may compensate for the impaired functionality, thus maintaining immune tolerance to the tumor.

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 research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Jeffrey Schlom, Building 10, Room 8B09, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. E-mail address: js141c{at}nih.gov

³ Abbreviations used in this paper: Treg, regulatory T; Efna1, ephrin A1; GITR, glucocorticoid-induced TNF receptor; ITK, IL-2-inducible kinase; MFI, mean fluorescence intensity.