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* Division of Molecular Immunology and
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; and
Immunomodulation Research Center, University of Ulsan, Ulsan, Korea
Members of the TNFR family are thought to deliver costimulatory signals to T cells and modulate their function and survival. In this study, we compare the role of two closely related TNFR family molecules, OX40 and 4-1BB, in generating effector CD8 T cells to Ag delivered by adenovirus. OX40 and 4-1BB were both induced on responding naive CD8 T cells, but 4-1BB exhibited faster and more sustained kinetics than OX40. OX40-deficient CD8 T cells initially expanded normally; however, their accumulation and survival at late times in the primary response was significantly impaired. In contrast, 4-1BB-deficient CD8 T cells displayed hyperresponsiveness, expanding more than wild-type cells. The 4-1BB-deficient CD8 T cells also showed enhanced maturation attributes, whereas OX40-deficient CD8 T cells had multiple defects in the expression of effector cell surface markers, the synthesis of cytokines, and in cytotoxic activity. These results suggest that, in contrast to current ideas, OX40 and 4-1BB can have a clear functional dichotomy in modulating effector CD8 T cell responses. OX40 can positively regulate effector function and late accumulation/survival, whereas 4-1BB can initially operate in a negative manner to limit primary CD8 responses.
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 Grant AI42944 from the National Institutes of Health (to M.C.) and by Grant R01 EY013325 from the National Institutes of Health, by the Science Research Center Fund from the Korea Science & Engineering Foundation, and by Grant KRF-2005-084-E00001 from the Korea Research Foundation (to B.S.K.).
2 Address correspondence and reprint requests to Dr. Michael Croft, Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121. E-mail address: mick{at}liai.org
3 Abbreviations used in this paper: HVEM, herpesvirus entry mediator; OX40L, OX40 ligand; LCMV, lymphocytic choriomeningitis virus; 4-1BBL, 4-1BB ligand; Ad-mOVA, recombinant defective type 5 adenovirus expressing membrane-bound OVA; LN, lymph node; BTLA, B and T lymphocyte attenuator.
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