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CD69⁺CD4⁺CD25^– T Cells, a New Subset of Regulatory T Cells, Suppress T Cell Proliferation through Membrane-Bound TGF-β1¹

National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai, People’s Republic of China

The underlying mechanisms of tumor-induced immune suppression need to be fully understood. Regulatory T (Treg) cells have been shown to play an important role in tumor immune escape. Until now, many subsets of Treg cells have been described that can suppress T cell response via different mechanisms. CD69 is generally regarded as one of the activating markers; however, recent studies show that CD69 may exert regulatory function in the immune response. In this study, we have identified tumor-induced CD69⁺CD4⁺CD25^– T cells as a new subset of CD4⁺ Treg cells. CD69⁺CD4⁺CD25^– T cells increase dramatically along tumor progression, with up to 40% of CD4⁺ T cells in the advanced tumor-bearing mice. Distinct from the previously described CD4⁺ Treg cell subsets, CD69⁺CD4⁺CD25^– T cells express high CD122, but they do not express Foxp3 and secrete IL-10, TGF-β1, IL-2, and IFN-. CD69⁺CD4⁺CD25^– T cells are hyporesponsive and can suppress CD4⁺ T cell proliferation in a cell-cell contact manner. Interestingly, the fixed CD69⁺CD4⁺CD25^– T cells still have suppressive activity, and neutralizing Abs against TGF-β1 can block their suppressive activity. We found that CD69⁺CD4⁺CD25^– T cells express membrane-bound TGF-β1, which mediates suppression of T cell proliferation. Furthermore, engagement of CD69 maintains high expression of membrane-bound TGF-β1 on CD69⁺CD4⁺CD25^– T cells via ERK activation. Our results demonstrate that CD69⁺CD4⁺CD25^– T cells act as a new subset of regulatory CD4⁺ T cells, with distinct characteristics of negative expression of Foxp3, no secretion of IL-10, but high expression of CD122 and membrane-bound TGF-β1. Our data contribute to the better understanding of mechanisms for tumor immune 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 was supported by grants from the National Natural Science Foundation of China (30672386, 30572121, 30721091), National Key Basic Research Program of China (2007CB512403), and Shanghai Committee of Science and Technology (08QA14002).

² Y.H. and Q.G. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Xuetao Cao, National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People’s Republic of China. E-mail address: caoxt{at}public3.sta.net.cn

⁴ Abbreviations used in this paper: Treg, regulatory T; maDC, mature dendritic cell; MFI, mean fluorescence intensity; MLN, mesenteric lymph node; MNC, mononuclear cell; 7-AAD, 7-aminoactinomycin D.

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