Role of 4-1BB (CD 137) in the functional activation of cord blood CD28-CD8+ T cells

Abstract

The 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 activationinduced 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 ligandexpressing Epstein-Barr virus (EBV)transformed B-cell line was almost completely abrogated by 4-1BB-Fc a soluble form of 4-1 BB, 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. © 2002 by The American Society of Hematology.