International Immunology, Vol. 14, No. 10, pp. 1155-1167,
October 2002
© 2002 Japanese Society for Immunology
4-1BB co-stimulation enhances human CD8+ T cell priming by augmenting the proliferation and survival of effector CD8+ T cells
1 Barbara Ann Karmanos Cancer Institute, Department of Immunology Microbiology, and 2 Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA 3 Emory Vaccine Center, Department of Surgery, Emory University, Atlanta, GA 30322, USA 4 INSERM U362, Institut Gustave Roussy, 94805 Villejuif Cedex, France
Correspondence to: A. Galy, INSERM U362, Institut Gustave Roussy PR1, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. E-mail: agaly{at}igr.fr
Transmitting editor: G. Trinchieri
Interactions between 4-1BB and its ligand, 4-1BBL, enhance CD8+ T cell-mediated antiviral and antitumor immunity in vivo. However, mechanisms regulating the priming of CD8+ T cell responses by 4-1BB remain unclear, particularly in humans. The 4-1BB receptor was undetectable on naive or resting human CD8+ T cells and induced in vitro by TCR triggering. Naive cord blood cells were therefore primed in vitro against peptides or cellular antigens and then co-stimulated with 4-1BBL or agonistic antibodies. Co-stimulation enhanced effector function such as IFN-
production and cytotoxicity by augmenting numbers of antigen-specific and effector CD8+ T cells. OKT3 responses also showed reduced cell death and revealed that the proliferation of CD8+ T cells required two independently regulated events. One, the induction of IL-2 production, could be directly triggered by 4-1BB engagement on CD8+ T cells in the absence of accessory cells. The other, expression of CD25, was induced with variable efficacy by accessory cells. Thus, suboptimal accessory cells and 4-1BB co-stimulation combined their effects to enhance IL-2 production and proliferation. Reduced apoptosis observed after co-stimulation in the presence of accessory cells correlated with increased levels of Bcl-XL in CD8+ T cells, while Bcl-2 expression remained unchanged. Altogether, 4-1BB enhanced expansion, survival and effector functions of newly primed CD8+ T cells, acting in part directly on these cells. As 4-1BB triggering could be protracted from the TCR signal, 4-1BB agonists may function through these mechanisms to enhance or rescue suboptimal immune responses.
Keywords: 4-1BB, co-stimulation, human CD8+ T cell
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