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Modulation of CD103 Expression on Human Colon Carcinoma-Specific CTL¹

Khoon-Lin Ling^2,*, Nicolas Dulphy^2,*, Pru Bahl^*, Mariolina Salio^*, Kevin Maskell^*, Juan Piris, Bryan F. Warren, Bruce D. George, Neil J. Mortensen and Vincenzo Cerundolo^3,*

^* Tumor Immunology Group, Human Immunology Unit, Weatherall Institute of Molecular Medicine, Department of Cellular Pathology, and Department of Colorectal Surgery, John Radcliffe Hospital, Oxford, United Kingdom

Recent results have shown a correlation between survival and frequency of tumor-infiltrating T cells in colorectal cancer patients. However, the mechanisms controlling the ability of human T lymphocytes to infiltrate colon carcinoma remain unclear. Although, it is known that expression of the integrin CD103_E/₇ by intraepithelial lymphocytes controls the retention of lymphocytes in epithelial layers, very little is known about the expression of intestinal homing receptors in human T lymphocytes. In particular, it remains unknown whether expression of CD103/₇ by human colon cancer-specific T lymphocytes is controlled by recognition of tumor Ags and is imprinted during T cell priming, facilitating its expression during memory T cell activation. In this study, we demonstrate that expression of CD103/₇ in human colon carcinoma-specific CTL is synergistically enhanced by the simultaneous TGF-1 stimulation and Ag recognition. These results were confirmed by using a panel of human CTL clones. Finally, we show that priming of naive CD8⁺ T cells in the presence of TGF-1 ensures up-regulation of CD103/₇ in recall responses, at concentrations of TGF-1 significantly lower than those required by memory T cells primed in the absence of TGF-1. These results indicate a role of TGF-1 during T cell priming in modulating expression of CD103/₇ and controlling retention of human memory CD8⁺ T cells into tumor epithelium.

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 the Cancer Research UK (Programme Grant C399), Medical Research Council and the U.S. Cancer Research Institute. K.-L.L. received a fellowship from the Singapore National Medical Research Council.

² K.-L.L. and N.D. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Vincenzo Cerundolo, Weatherall Institute of Molecular Medicine, Oxford, OX3 9DS, U.K. E-mail address: vincenzo.cerundolo{at}molecular-medicine.oxford.ac.uk

⁴ Abbreviations used in this paper: DC, dendritic cell; GVDH, graft-vs-host disease; MLN, mesenteric lymph node; PBL, peripheral blood lymphocyte; rhIL-2, recombinant human IL-2; MLTC, mixed lymphocyte tumor culture; TIL, tumor-infiltrating lymphocyte.