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Activation-Induced Cell Death Limits Effector Function of CD4 Tumor-Specific T Cells¹

Rebecca R. Saff^*, Elena S. Spanjaard^*, Andreas M. Hohlbaum and Ann Marshak-Rothstein^2,*

^* Department of Microbiology, Boston University School of Medicine, Boston, MA 02118; and Pieris Proteolab, Freising-Weihenstephan, Germany

A number of studies have documented a critical role for tumor-specific CD4⁺ cells in the augmentation of immunotherapeutic effector mechanisms. However, in the context of an extensive tumor burden, chronic stimulation of such CD4⁺ T cells often leads to the up-regulation of both Fas and Fas ligand, and coexpression of these molecules can potentially result in activation-induced cell death and the subsequent loss of effector activity. To evaluate the importance of T cell persistence in an experimental model of immunotherapy, we used DO11 Th1 cells from wild-type, Fas-deficient, and Fas ligand-deficient mice as effector populations specific for a model tumor Ag consisting of an OVA-derived transmembrane fusion protein. We found that the prolonged survival of Fas-deficient DO11 Th1 cells led to a more sustained tumor-specific response both in vitro and in vivo. Importantly, both Fas- and Fas ligand-deficient Th1 cells delayed tumor growth and cause regression of established tumors more effectively than wild-type Th1 cells, indicating that resistance to activation-induced cell death significantly enhances T cell effector activity.

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