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Cytokine Deprivation of Naive CD8⁺ T Cells Promotes Minimal Cell Cycling but Maximal Cytokine Synthesis and Autonomous Proliferation Subsequently: A Mechanism of Self-Regulation¹

Subash Sad^2,*, and Lakshmi Krishnan^*

^* Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada; and Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

Naive CD8⁺ T cells differentiate into effectors secreting various cytokines that aid their function. IL-2, but not IL-15, promoted this differentiation of naive CD8⁺ T cells into effectors. However, the amount of IL-2 present during differentiation had a dichotomous effect on their subsequent function. High concentrations of IL-2 enhanced proliferation and cell cycling initially, but the effectors subsequently failed to produce cytokines and proliferate autonomously, although CD28 expression was maintained. In contrast, suboptimal amounts of IL-2 during priming promoted apoptosis, little proliferation and cell cycling, yet the CD8⁺ effectors generated produced high levels of cytokines and proliferated autonomously. Interestingly, the effects of IL-2 on naive CD8⁺ T cells were totally opposite those on naive CD4⁺ T cells. Although IL-2 impaired cytokine synthesis by CD8⁺ T cells, the expression of LFA1 and CD44 as well as Fas-dependent cytotoxicity were enhanced. However, loss of cytokine synthesis was not due to increased cytotoxicity, as inhibition occurred even in the absence of perforin/FasL. Interestingly, CD8⁺ effectors secreting reduced amounts of cytokines exhibited enhanced IL-2R, but reduced IL-2Rß, expression. Furthermore, sorted CD8⁺ IL-2R^high cells secreted less cytokines than IL-2R^low cells. These results suggest that the presence of excessive IL-2 during the activation of naive CD8⁺ T cells, while promoting cell cycling initially, may compromise long-term immunity.

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