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Membrane-Associated TGF-1 Inhibits Human Memory T Cell Signaling in Malignant and Nonmalignant Inflammatory Microenvironments¹

Department of Microbiology and Immunology, State University of New York, Buffalo, NY 14214

TGF-1 is present on cells derived from the microenvironment of human lung tumors and nonmalignant inflammatory tissues. We establish that this cell-associated cytokine mediates hyporesponsiveness of the memory T cells in these microenvironments in situ by blocking TCR signaling. T cells derived from these tissues failed to translocate NF-B to the nucleus in response to CD3 + CD28 cross-linking. This nonresponsiveness was reversed by an anti-TGF-1-neutralizing Ab. Refractoriness of the memory T cells to TCR activation was also reversed by the removal of TGF-1 by briefly pulsing the cells in a low pH buffer. Addition of exogenous TGF-1 to eluted T cells re-established their nonresponsive state. Neither TGF-1, anti-TGF-1 Ab, nor low pH affected TCR signaling potential of peripheral blood T cells. We conclude that TGF-1 mediates a physiologically relevant regulatory mechanism, selective for memory T cells present in the tumor microenvironment and nonmalignant chronic inflammatory tissues.

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 U.S. Public Health Service Grants RO1-CA10897, The John R. Oishei Foundation, the Mary Kay Ash Foundation (to R.B.B.), and National Research Service Award Training Grant AIO7614 (to L.B.).

² Address correspondence and reprint requests to Dr. Richard B. Bankert, Department of Microbiology and Immunology, 138 Farber Hall, State University of New York, 3435 Main Street, Buffalo, NY 14214. E-mail address: rbankert{at}buffalo.edu

³ Abbreviation used in this paper: T_Reg, regulatory T cell.

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