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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2001-11-0136.
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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3253-3260
IMMUNOBIOLOGY
Role of 4-1BB (CD137) in the functional activation of cord
blood CD28 CD8+ T cells
Young-June Kim,
Randy R. Brutkiewicz, and
Hal E. Broxmeyer
From the Department of Microbiology and Immunology,
Walther Oncology Center, Indiana University School of Medicine, and the
Walther Cancer Institute, Indianapolis, IN.
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 CD28CD8+ 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.
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