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Enhanced Levels of Costimulation Lead to Reduced Effector/Memory CD8⁺ T Cell Functionality¹

Sven Mostböck^*, Silvia Vidal, Jeffrey Schlom^2,* and Helen Sabzevari^*

^* Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and Department of Immunology, Hospital Sant Pau, Barcelona, Spain

The role of different levels of costimulation in conjunction with signal 1 in the activation of memory CD8⁺ T cells remains elusive. In this study, we demonstrate, in a mouse model with the influenza nucleoprotein epitope NP68, that mouse early memory (effector/memory) CD8⁺ T cells that were generated with high levels of costimulation have reduced CTL functionality compared with those that were generated with low levels of costimulation. This reduction is associated with increased phosphorylation of the negative regulatory site 292 on Zap70 and a decrease in granzyme B levels. Furthermore, we show that enhanced costimulation reduces proliferation and cytokine production of effector/memory CD8⁺ T cells in response to intermediate and weak TCR stimulation, in contrast to previously described positive effects of costimulation on naive CD8⁺ T cells. This effect is associated with the expression of ICAM-1 on APCs. Together, our results indicate that enhanced costimulation can lead to reduced functionality in effector/memory CD8⁺ T cells. This compromised effector function of effector/memory CD8⁺ T cells in response to high levels of costimulation can have important implications for designing immunotherapeutic strategies to enhance immune 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 the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

² Address correspondence and reprint requests to Dr. Jeffrey Schlom, Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Building 10 Room 8B09, 10 Center Drive, Bethesda, MD 20892. E-mail address: js141c{at}nih.gov

³ Abbreviations used in this paper: APL, altered peptide ligand; WT, wild type; FP-WT, WT fowlpox virus; MOI, multiplicity of infection; TRICOM, triad of costimulatory molecules (ICAM-1, B7.1, LFA-3); LN, lymph node; DC, dendritic cell.

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The JI 2007 179: 3389-3390. [Full Text]  

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