Role of 4-1BB (CD137) in the functional activation of cord blood CD28−CD8+ T cells

Abstract

AbstractThe CD28− subset of CD8+ T cells is associated with cytotoxic T lymphocyte (CTL) effector function. We investigated a potential role for 4-1BB, a costimulatory molecule structurally related to members of the tumor necrosis factor (TNF) receptor family, in the generation and functional activation of CD28− CTLs by using human cord blood (CB) cells composed exclusively of naive CD8+ T cells with few or no CD28− CTLs. The 4-1BB was induced preferentially on the CB CD28−CD8+ T cells when CD28 down-regulation was induced by interleukin 15 (IL-15) and IL-12 stimulation. Anti–4-1BB costimulation induced dramatic phenotypic changes in the CD28− CTLs, including restoration of CD28 expression as well as that of memory markers such as CD45RO and CC chemokine receptor 6 (CCR6). Anti–4-1BB costimulation also promoted long-term survival of CD28− CTLs, which were sensitive to activation-induced cell death upon anti-CD3 stimulation. The memory-type CD28+CTLs induced by anti–4-1BB costimulation acquired a greatly enhanced content of granzyme B, a cytolytic mediator, and enhanced cytotoxic activity as compared with CD28− CTLs. Strong cytotoxicity of memory-type CTLs to a 4-1BB ligand–expressing Epstein-Barr virus (EBV)–transformed B-cell line was almost completely abrogated by 4-1BB–Fc, a soluble form of 4-1BB, suggesting involvement of 4-1BB in cytolytic processes. Taken all together, our results suggest that 4-1BB plays a role in the differentiation of effector memory CTLs.