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Infiltration of a Mesothelioma by IFN--Producing Cells and Tumor Rejection after Depletion of Regulatory T Cells¹

Geordie Rudge^*, Simon P. Barrett^*, Bernadette Scott and Ian R. van Driel^2,*

^* Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia; and Monash Institute of Medical Research, Monash Medical Centre, Clayton, Australia

Depletion of CD4⁺CD25⁺Foxp3⁺ regulatory T cells (CD25⁺ T_reg) with an anti-CD25 Ab results in immune-mediated rejection of tolerogenic solid tumors. In this study, we have examined the immune response to a mesothelioma tumor in mice after depletion of CD25⁺ cells to elucidate the cellular mechanisms of CD25⁺ T_reg, a subject over which there is currently much conjecture. Tumor rejection was found to be primarily due to the action of CD8⁺ T cells, although CD4⁺ cells appeared to play some role. Depletion of CD25⁺ cells resulted in an accumulation in tumor tissue of CD4⁺ and CD8⁺ T cells and NK cells that were producing the potent antitumor cytokine IFN-. Invasion of tumors by CD8⁺ T cells was partially dependent on the presence of CD4⁺ T cells. Although a significant increase in the proliferation and number of tumor-specific CD8⁺ T cells was observed in lymph nodes draining the tumor of anti-CD25-treated mice, this effect was relatively modest compared with the large increase in IFN--producing T cells found in tumor tissue, which suggests that the migration of T cells into tumor tissue may also have been altered. Depletion of CD25⁺ cells did not appear to modulate antitumor CTL activity on a per cell basis. Our data suggests that CD25⁺ T_reg limit the accumulation of activated T cells producing IFN- in the tumor tissue and, to a lesser extent, activation and/or rate of mitosis of tumor-specific T cells in lymph nodes.

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 National Health and Medical Research Council of Australia.

² Address correspondence and reprint requests to Dr. Ian R. van Driel, Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia. E-mail address: i.vandriel{at}unimelb.edu.au

³ Abbreviations used in this paper: CD25⁺ T_reg, CD4⁺CD25⁺Foxp3⁺ regulatory T cells; HA, hemagglutinin.

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