Role of 4-1BB (CD137) in the functional activation of cord blood CD28(-)CD8(+) T cells.
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 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.
Kim
Young-June
YJ
Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202-5254, USA.
Brutkiewicz
Randy R
RR
Broxmeyer
Hal E
HE
D015703:Antigens, CD; D018106:CD28 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D002470:Cell Survival; D003602:Cytotoxicity, Immunologic; D005312:Fetal Blood / Q000166:cytology* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D053804:Granzymes; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D007156:Immunologic Memory; D007231:Infant, Newborn; D018664:Interleukin-12 / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology; D020014:K562 Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012697:Serine Endopeptidases / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D015703:Antigens, CD; D018106:CD28 Antigens; D016827:CD8 Antigens; D019409:Interleukin-15; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D018664:Interleukin-12; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases