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Human CD4⁺ T Cells Recognize an Epitope within -Fetoprotein Sequence and Develop into TGF-β-Producing CD4⁺ T Cells¹

Akeel Alisa^*, Sandra Boswell^*, Ansar A. Pathan, Lakshmana Ayaru^*, Roger Williams^* and Shahriar Behboudi^2,*

^* Department of Medicine, Institute of Hepatology, University College London, London, United Kingdom; and Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, United Kingdom

There is limited information on the influence of tumor growth on the expansion of tumor-specific TGF-β-producing CD4⁺ T cells in humans. -Fetoprotein (AFP) is an oncofetal Ag and has intrinsic immunoregulatory properties. In this study, we report the identification and characterization of subsets of CD4⁺ T cells that recognize an epitope within the AFP sequence (AFP_46–55) and develop into TGF-β-producing CD4⁺ T cells. In a peptide-specific and dose-dependent manner, AFP_46–55 CD4⁺ T cells produce TGF-β, GM-CSF, and IL-2 but not Th1-, Th2-, Th17-, or Tr1-type cytokines. These cells express CTLA-4 and glucocorticoid-induced TNR receptor and inhibit T cell proliferation in a contact-dependent manner. In this study, we show that the frequency of AFP_46–55 CD4⁺ T cells is significantly higher (p = 001) in patients with hepatocellular carcinoma than in healthy donors, suggesting that these cells are expanded in response to tumor Ag. In contrast, tumor necrosis-inducing treatments that are shown to improve survival rate can shift the Th1/TGF-β-producing CD4⁺ T cell balance in favor of Th1 responses. Our data demonstrate that tumor Ags may contain epitopes which activate the expansion of inducible regulatory T cells, leading to evasion of tumor control.

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 study was supported by a project grant from Association for International Cancer Research and the de Laszlo Foundation (to S.Be.). This work was undertaken at the University College London, which received funding from the Health’s Biomedical Research Centers funding scheme.

² Address correspondence and reprint requests to Dr. Shahriar Behboudi, Royal Free and University College School of Medicine, 69-75 Chenies Mews, WC1E 6HX London, U.K. E-mail address: s.behboudi{at}ucl.ac.uk

³ Abbreviations used in this paper: Treg, regulatory T cell; AFP, -fetoprotein; HCC, hepatocellular carcinoma; GITR, glucocorticoid-induced TNF receptor; HD, healthy donor; TAE, transarterial embolization.