4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy

A costimulatory member of the TNFR family, 4-1BB, is expressed on activated T cells. Although some reports have suggested that 4-1BB is primarily invo lved in CD8 T cell activation, in this report we demonstrate that both CD4 and CD8 T cells respond to 4-1BB ligand (4-1BBL) with similar efficacy. CD4 and CD8 TCR transgenic T cells up-regulate 4-1BB, OX40, and CD27 and respo nd to 4-1BBL-mediated costimulation during a primary response to peptide Ag . 4-1BBL enhanced proliferation, cytokine production, and CTL effector func tion of TCR transgenic T cells. To compare CD4 vs CD8 responses to 4-1BBL u nder similar conditions of antigenic stimulation, we performed MLRs with pu rified CD4 or CD8 responders from CD28(+/+) and CD28(-/-) mice. We found th at CD8 T cells produced IL-2 and IFN-gamma in a 4-1BBL-dependent manner, wh ereas under the same conditions the CD4 T cells produced IL-2 and IL-4. 4-1 BBL promoted survival of CD4 and CD8 T cells, particularly at late stages o f the MLR. CD4 and CD8 T cells both responded to anti-CD3 plus s4-1BBL with a similar cytokine profile as observed in the MLR. CD4 and CD8 T cells exh ibited enhanced proliferation and earlier cell division when stimulated wit h anti-CD3 plus anti-CD28 compared with anti-CD3 plus 4-1BBL, and both subs ets responded comparably to anti-CD3 plus 4-1BBL. These data support the id ea that CD28 plays a primary role in initial T cell expansion, whereas 4-1B B/4-1BBL sustains both CD4 and CD8 T cell responses, as well as enhances ce ll division and T cell effector function.