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* Department of Immunology, University of Toronto, Toronto, Canada;
Immunodeficiency Service and Division of Hematology, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada;
Research Institute of the McGill University Health Center, Montreal, Quebec, Canada; and
Departement de Microbiologie et Immunologie, Universite de Montreal, Montreal, Quebec, Canada
During chronic infection, HIV-specific CD8 T cells exhibit progressive signs of functional impairment, attributed to persistent antigenic stimulation, up-regulation of the inhibitory receptor PD-1, and declining T cell help. Strategies that directly improve CD8 T cell function offer the potential of restoring immune control of HIV. Although PD-1 expression has been identified as a cause of functional impairment in HIV, in this study, PD-1 expression was observed on only a subfraction of HIV-specific CD8 T cells in a subfraction of donors, whereas HIV-specific CTL from all donors exhibited a limited repertoire of effector functions. CD137L (4-1BBL) is emerging as an important stimulator of antiviral CD8 T cell responses. Regardless of the PD-1 status of the donors, here we show that 4-1BBL, when combined with CD80 or CD70, expands a population of Ag-specific CD8 T cells expressing multiple markers of effector function, from the functionally impaired starting population. In contrast, CD70 in combination with CD80 was insufficient for these effects and the related TNF family ligand, LIGHT, had negligible activity. The unique contribution of 4-1BBL correlated with down-regulation of the proapoptotic molecule Bim in activated CD8 T cells. Decreasing the level of TNFR-associated factor 1 in T cells using small interfering RNA resulted in increased levels of Bim in the 4-1BBL-stimulated T cells. Thus, costimulation via 4-1BBL leads to TNFR-associated factor 1-dependent Bim down-modulation in T cells, resulting in increased T cell expansion. These studies identify 4-1BBL as a critical component in therapeutic strategies aimed at improving CD8 T cell function.
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 74492 from the Canadian Institutes for Health Research (to T.H.W.) and by the Canadian Network for Vaccines and Immunotherapeutics.
2 Current address: Sanofi-Pasteur, Toronto, Ontario, Canada.
3 Address correspondence and reprint requests to Dr. Tania H. Watts, Department of Immunology, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada, M5S 1A8. E-mail address: tania.watts{at}utoronto.ca
4 Abbreviations used in this paper: TRAF1, TNFR-associated factor 1; LTβR, lymphotoxin β receptor; MHC I, MHC class I; MHC II, MHC class II; h, human; MFI, median fluorescence intensity; HVEM, herpes virus entry mediator; siRNA, small interfering RNA; AdV, adenovirus.
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