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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2001-11-0136.
Submitted December 4, 2001
Accepted June 4, 2002
Role of 4-1BB (CD137) in the functional activation of cord blood CD28-negative CD8+ T cells
Young-June Kim, Randy R Brutkiewicz, and Hal E Broxmeyer*
Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA; Walther Cancer Institute, Indianapolis, IN, USA
* Corresponding author; email: hbroxmey{at}iupui.edu.
The CD28-negative subset of CD8+ T cells is associated with cytotoxic T lymphocyte (CTL) effector function. We investigated a potential role for 4-1BB, a co-stimulatory molecule structurally related to members of the TNF receptor family, in the generation and functional activation of CD28-negative CTLs by using human cord blood (CB) cells comprised exclusively of naive CD8+ T cells with little or no CD28-negative CTLs. 4-1BB was induced preferentially on the CB CD28-negative CD8+ T cells when CD28 down-regulation was induced by IL-15 and IL-12 stimulation. Anti-4-1BB co-stimulation induced dramatic phenotypic changes in the CD28-negative CTLs, including restoration of CD28 expression as well as that of memory markers such as CD45RO and CCR6. Anti-4-1BB co-stimulation also promoted long-term survival of CD28-negative CTLs, which were sensitive to activation-induced cell death upon anti-CD3 stimulation. The memory-type CD28-positive CTLs induced by anti-4-1BB co-stimulation acquired a greatly enhanced content of granzyme B, a cytolytic mediator, and cytotoxic activity as compared to CD28-negative CTLs. Strong cytotoxicity of memory-type CTLs to a 4-1BB ligand-expressing 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 altogether, our results suggest that 4-1BB plays a role in the differentiation of effector memory CTLs.
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