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* Department of Immunology and
Division of Endocrinology, Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030;
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92121;
Immunomodulation Research Center, University of Ulsan, Ulsan, South Korea; and
¶ Department of Surgery and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329
The TNFR superfamily members 4-1BB (CD137) and OX40 (CD134) are costimulatory molecules that potently boost CD8 and CD4 T cell responses. Concomitant therapeutic administration of agonist anti-CD137 and -CD134 mAbs mediates rejection of established tumors and fosters powerful CD8 T cell responses. To reveal the mechanism, the role of CD137 expression by specific CD8 T cells was determined to be essential for optimal clonal expansion and accumulation of effector cells. Nonetheless, dual costimulation induced production of supereffector CD8 T cells when either the specific T cells or the host alone bore CD137. Perhaps surprisingly, the total absence of CD137 prevented anti-CD134 augmentation of supereffector differentiation demonstrating an unappreciated link between these related pathways. Ultimately, it was reasoned that these powerful dual costimulatory responses involved common 
family members, and we show substantial increases of CD25 and IL-7R
-chain expression by the specific CD8 T cells. To investigate this further, it was shown that IL-7 mediated T cell accumulation, but importantly, a gradual and preferential effect of survival was directed toward supereffector CD8 T cells. In fact, a clear enhancement of effector differentiation was demonstrated to be proportional to the increasing amount of IL-7R expression by the specific CD8 T cells. Therefore, dual costimulation through CD137 and CD134 drives production and survival of supereffector CD8 T cells through a distinct IL-7-dependent pathway.
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 Grants R01 AI42858 and AI52108 (to A.T.V.).
2 Address correspondence and reprint requests to Dr. Anthony T. Vella, Department of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030.
3 Abbreviations used in this paper: DC, dendritic cell; c, common ; PLN, peripheral lymph node; MLN, mesenteric lymph node; WT, wild type.
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