4-1BB Costimulatory Signals Preferentially Induce CD8+ T Cell Proliferation and Lead to the Amplification In Vivo of Cytotoxic T Cell Responses

WW Shuford, K Klussman, DD Tritchler… - The Journal of …, 1997 - rupress.org
WW Shuford, K Klussman, DD Tritchler, DT Loo, J Chalupny, AW Siadak, TJ Brown…
The Journal of experimental medicine, 1997rupress.org
The 4-1BB receptor is an inducible type I membrane protein and member of the tumor
necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+
and CD8+ T cells after antigen-or mitogen-induced activation. Cross-linking of 4-1BB and
the T cell receptor (TCR) on activated T cells has been shown to deliver a costimulatory
signal to T cells. Here, we expand upon previously published studies by demonstrating that
CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early …
The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation. Cross-linking of 4-1BB and the T cell receptor (TCR) on activated T cells has been shown to deliver a costimulatory signal to T cells. Here, we expand upon previously published studies by demonstrating that CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB. In comparison, CD28-mediated costimulatory signals appear to function in a reciprocal manner to those induced through 4-1BB costimulation. In vivo examination of the effects of anti-4-1BB monoclonal antibodies (mAbs) on antigen-induced T cell activation have shown that the administration of epitope-specific anti-4-1BB mAbs amplified the generation of H-2d–specific cytotoxic T cells in a murine model of acute graft versus host disease (GVHD) and enhanced the rapidity of cardiac allograft or skin transplant rejection in mice. Cytokine analysis of in vitro activated CD4+ and CD8+ T cells revealed that anti-4-1BB costimulation markedly enhanced interferon-γ production by CD8+ T cells and that anti-4-1BB mediated proliferation of CD8+ T cells appears to be IL-2 independent. The results of these studies suggest that regulatory signals delivered by the 4-1BB receptor play an important role in the regulation of cytotoxic T cells in cellular immune responses to antigen.
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