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IL-21 Sustains CD28 Expression on IL-15-Activated Human Naive CD8⁺ T Cells

Nuno L. Alves^1,*,, Fernando A. Arosa and René A. W. van Lier^*

^* Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands; and Institute for Molecular and Cell Biology, Porto, Portugal

Human naive CD8⁺ T cells are able to respond in an Ag-independent manner to IL-7 and IL-15. Whereas IL-7 largely maintains CD8⁺ T cells in a naive phenotype, IL-15 drives these cells to an effector phenotype characterized, among other features, by down-regulation of the costimulatory molecule CD28. We evaluated the influence of the CD4⁺ Th cell-derived common -chain cytokine IL-21 on cytokine-induced naive CD8⁺ T cell activation. Stimulation with IL-21 did not induce division and only slightly increased IL-15-induced proliferation of naive CD8⁺ T cells. Strikingly, however, IL-15-induced down-modulation of CD28 was completely prevented by IL-21 at the protein and transcriptional level. Subsequent stimulation via combined TCR/CD3 and CD28 triggering led to a markedly higher production of IL-2 and IFN- in IL-15/IL-21-stimulated cells compared with IL-15-stimulated T cells. Our data show that IL-21 modulates the phenotype of naive CD8⁺ T cells that have undergone IL-15 induced homeostatic proliferation and preserves their responsiveness to CD28 ligands.

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