Costimulation of human CD28- T cells by 4-1BB ligand

The T cell surface protein CD28 provides a critical costimulatory signal for T cell activation. With age, humans accumulate increasing numbers of CD28(-) T cells, and this loss of CD28 expression is exacerbated certain disease states, such as HIV infection, autoimmune conditions or cancer. It is unclear whether CD28(-) T cells represent terminally differentiated effector cells or whether they remain sensitive to costimulation by CD28-independent pathways. Here, we demonstrate that 4-1 BB ligand can costimulate human CD28(-) T cells, resulting in cell division, inflammatory cytokine production, increased perforin levels, enhancement of cytolytic effector function, as well as the up-regulation of the anti-apoptotic protein Bcl-X-L. Thus, human CD28(-)T cells can respond to costimulatory signals and as such become attractive targets for therapeutic intervention, particularly in chronic infectious and inflammatory diseases where large numbers of these cells accumulate.