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Fc Receptor-Like 3 Protein Expressed on IL-2 Nonresponsive Subset of Human Regulatory T Cells¹

Satoshi Nagata^2,3,*,, Tomoko Ise^2,*, and Ira Pastan^*

^* Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57105

Fc receptor-like 3 (FCRL3) is a cell surface protein homologous to Fc receptors. The FCRL3 gene is present in humans but not in mice. We found that FCRL3 protein is expressed on 40% of human naturally occurring CD4⁺ regulatory T (nTreg) cells (CD4⁺CD25⁺CD127^low). Sorted nTreg cells with the surface phenotype FCRL3⁺ and FCRL3^– were both hypoproliferative to TCR stimulation and both suppressive on proliferation of conventional T cells (CD4⁺CD25^–) in vitro. They both expressed forkhead box p3 (Foxp3) protein, the intracellular regulatory T cell marker. However, in contrast to FCRL3^– nTreg cells, FCRL3⁺ nTreg cells were not stimulated to proliferate by the addition of exogenous IL-2. In addition, Foxp3⁺ cells induced from conventional T cells by TGF-β treatment did not exhibit FCRL3 expression. These results suggest that the FCRL3⁺ subset of human nTreg cells identified in this study arise in vivo and Foxp3 expression alone is not sufficient to induce FCRL3 expression. FCRL3 may be involved in human-specific mechanisms to control the generation of nTreg cells.

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 National Institutes of Health, National Cancer Institute, Center for Cancer Research.

² S.N. and T.I. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Satoshi Nagata, Cancer Biology Research Center, Sanford Research/USD, 1400 West 22nd Street, Room L08, Sioux Falls, SD 57105. E-mail address: nagatas{at}sanfordhealth.org

⁴ Abbreviations used in this paper: FCRL, Fc receptor-like; Foxp3, forkhead box p3; GITR, glucocorticoid-induced TNFR family-related protein; nTreg, naturally occurring CD4⁺ regulatory T; Teff, T effector; Treg, regulatory T.

⁵ The online version of this article contains supplemental material.