HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900970v1 183/6/3720    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Wieckowski, E. U. Articles by Whiteside, T. L. PubMed PubMed Citation Articles by Wieckowski, E. U. Articles by Whiteside, T. L.

Tumor-Derived Microvesicles Promote Regulatory T Cell Expansion and Induce Apoptosis in Tumor-Reactive Activated CD8⁺ T Lymphocytes¹

Eva U. Wieckowski^*,, Carmen Visus, Marta Szajnik, Miroslaw J. Szczepanski, Walter J. Storkus^, and Theresa L. Whiteside^2,*,

^* Department of Pathology and Department of Dermatology, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213

Sera of patients with cancer contain membraneous microvesicles (MV) able to induce apoptosis of activated T cells by activating the Fas/Fas ligand pathway. However, the cellular origin of MV found in cancer patients’ sera varies as do their molecular and cellular profiles. To distinguish tumor-derived MV in cancer patients’ sera, we used MAGE 3/6⁺ present in tumors and MV. Molecular profiles of MAGE 3/6⁺ MV were compared in Western blots or by flow cytometry with those of MV secreted by dendritic cells or activated T cells. These profiles were found to be distinct for each cell type. Only tumor-derived MV were MAGE 3/6⁺ and were variably enriched in 42-kDa Fas ligand and MHC class I but not class II molecules. Effects of MV on signaling via the TCR and IL-2R and proliferation or apoptosis of activated primary T cells and T cell subsets were also assessed. Functions of activated CD8⁺ and CD4⁺ T lymphocytes were differentially modulated by tumor-derived MV. These MV inhibited signaling and proliferation of activated CD8⁺ but not CD4⁺ T cells and induced apoptosis of CD8⁺ T cells, including tumor-reactive, tetramer⁺CD8⁺ T cells as detected by flow cytometry for caspase activation and annexin V binding or by DNA fragmentation. Tumor-derived but not dendritic cell-derived MV induced the in vitro expansion of CD4⁺CD25⁺FOXP3⁺ T regulatory cells and enhanced their suppressor activity. The data suggest that tumor-derived MV induce immune suppression by promoting T regulatory cell expansion and the demise of antitumor CD8⁺ effector T cells, thus contributing to tumor escape.

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 is supported in part by the National Institutes of Health Grant P01 CA109688 (to T.L.W.). M.S. was supported by the National Heart, Lung, and Blood Institute-sponsored Production Assistance for Cellular Therapies Program N01-HB-37165.

² Address correspondence and reprint requests to Dr. Theresa L. Whiteside, University of Pittsburgh Cancer Institute Research Pavilion at the Hillman Cancer Center, 5117 Centre Avenue, Suite 1.27D, Pittsburgh, PA 15213-1863. E-mail address: whitesidetl{at}upmc.edu

³ Abbreviations used in this paper: MV, microvesicle; DC, dendritic cell; FasL, Fas ligand; IVS, in vitro stimulation; NC, normal control; SCCHN, head and neck squamous cell carcinoma; TAA, tumor-associated Ag; Treg, regulatory T cell; iDC, immature DC.

⁴ The online version of this article contains supplemental material.