Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+CD28– cytotoxic effector clones

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Abstract
CD8 T cells contain a distinct subset of CD8+CD28– cells. These cells are not present at birth and their frequency increases with age. They frequently contain expanded clones using various TCRαβ receptors and these clones can represent >50% of all CD8 cells, specially in old subjects or patients with chronic viral infections such as HIV-1. Herein, it is shown that a large fraction of CD8+CD28– cells expresses intracellular perforin by three-color flow cytometry, in particular when this subset is expanded. Together with their known ability to exert potent re-directed cytotoxicity, this indicates that CD8+CD28– T cells comprise cytotoxic effector cells. With BrdU labeling, we show that CD8+CD28– cells derive from CD8+CD28+ precursors in vitro. In addition, sorted CD8+CD28+ cells gave rise to a population of CD8+CD28– cells after allo-stimulation. Moreover, ex vivo CD8+CD28+ cells contain the majority of CD8 blasts, supporting the notion that they contain the proliferative precursors of CD8+CD28– cells. CD95 (Fas) expression was lower in CD8+CD28– cells, and this subset was less prone to spontaneous apoptosis in ex vivo samples and more resistant to activation-induced cell death induced by a superantigen in vitro. Thus, the persistence of expanded clones in vivo in the CD8+CD28– subset may be explained by antigen-driven differentiation from CD8+CD28+ memory precursors, with relative resistance to apoptosis as the clones become perforin+ effector cells.