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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0900475v1 183/10/6157    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 Hilchey, S. P. Articles by Bernstein, S. H. PubMed PubMed Citation Articles by Hilchey, S. P. Articles by Bernstein, S. H.

Human Follicular Lymphoma CD39⁺-Infiltrating T Cells Contribute to Adenosine-Mediated T Cell Hyporesponsiveness¹

Shannon P. Hilchey,^* James J. Kobie, Mathew R. Cochran, Shelley Secor-Socha, Jyh-Chiang E. Wang, Ollivier Hyrien, W. Richard Burack,^* Tim R. Mosmann, Sally A. Quataert, and Steven H. Bernstein^2*

^*James P. Wilmot Cancer Center, Lymphoma Biology Program, Division of Allergy, Immunology and Rheumatology, David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, and Department of Microbiology and Immunology, Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY 14642

Our previous work has demonstrated that human follicular lymphoma (FL) infiltrating T cells are anergic, in part due to suppression by regulatory T cells. In this study, we identify pericellular adenosine, interacting with T cell-associated G protein-coupled A_2A/B adenosine receptors (AR), as contributing to FL T cell hyporesponsiveness. In a subset of FL patient samples, treatment of lymph node mononuclear cells (LNMC) with specific A_2A/B AR antagonists results in an increase in IFN- or IL-2 secretion upon anti-CD3/CD28 Ab stimulation, as compared with that seen without inhibitors. In contrast, treatment with an A₁ AR antagonist had no effect on cytokine secretion. As the rate limiting step for adenosine generation from pericellular ATP is the ecto-ATPase CD39, we next show that inhibition of CD39 activity using the inhibitor ARL 67156 partially overcomes T cell hyporesponsiveness in a subset of patient samples. Phenotypic characterization of LNMC demonstrates populations of CD39-expressing CD4⁺ and CD8⁺ T cells, which are overrepresented in FL as compared with that seen in normal or reactive nodes, or normal peripheral blood. Thirty percent of the FL CD4⁺CD39⁺ T cells coexpress CD25^high and FOXP3 (consistent with regulatory T cells). Finally, FL or normal LNMC hydrolyze ATP in vitro, in a dose- and time-dependent fashion, with the rate of ATP consumption being associated with the degree of CD39⁺ T cell infiltration. Together, these results support the finding that the ATP-ectonucleotidase-adenosine system mediates T cell anergy in a human tumor. In addition, these studies suggest that the A_2A/B AR as well as CD39 are novel pharmacological targets for augmenting cancer immunotherapy.

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 in part by Grant 5-29712 from a University of Rochester Human Immunology Core Pilot Project, by Grants R01-CA122645 and R21 CA129936 from the U.S. Public Health Service, and by Grant P50-CA130805 from a SPORE in Lymphoma.

² Address correspondence and reprint requests to Dr. Steven H. Bernstein, Lymphoma Biology Program, James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642. E-mail address: Steven_Bernstein{at}urmc.rochester.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; FL, follicular lymphoma; NLN, normal lymph node; RLN, reactive lymph node; LNMC, lymph node mononuclear cell; AR, adenosine receptor; RLU, relative luminescent unit.