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Signal 3 Availability Limits the CD8 T Cell Response to a Solid Tumor¹

Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455

CD8 T cells need a third signal, along with Ag and costimulation, for effective survival and development of effector functions, and this can be provided by IL-12 or type I IFN. Adoptively transferred OT-I T cells, specific for H-2K^b and OVA, encounter Ag in the draining lymph nodes of mice with the OVA-expressing E.G7 tumor growing at a s.c. site. The OT-I cells respond by undergoing limited clonal expansion and development of effector functions (granzyme B expression and IFN- production), and they migrate to the tumor where they persist but fail to control tumor growth. In contrast, OT-I T cells deficient for both the IL-12 and type I IFN receptors expand only transiently and rapidly disappear. These results suggested that some signal 3 cytokine is available, but that it is insufficient to support a CTL response that can control tumor growth. Consistent with this, administration of IL-12 at day 10 of tumor growth resulted in a large and sustained expansion of wild-type OT-I cells with enhanced effector functions, and tumor growth was controlled. This did not occur when the OT-I cells lacked the IL-12 and type I IFN receptors, demonstrating that the therapeutic effect of IL-12 results from direct delivery of signal 3 to the CD8 T cells responding to tumor Ag in the signal 3-deficient environment of the tumor.

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 National Institutes of Health Grant R01 CA088956 (to M.F.M.) and National Cancer Institute Training Grant 2 T32 CA009138-31 (to M.Y.G.).

² Address correspondence to Dr. Julie M. Curtsinger, Center for Immunology, Box 334 Mayo, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail address: curts001{at}umn.edu

³ Abbreviations used in this paper: DLN, draining lymph node; GzmB, granzyme B; wt, wild type; RKO, receptor knockout; DC, dendritic cell; Treg, regulatory T cell; AINR, Ag-induced nonresponsiveness; LN, lymph node.

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