HUMAN 4-1BB REGULATES CD28 CO-STIMULATION TO PROMOTE TH1 CELL RESPONSES

Our present study provides evidence that the 4-1BB signal is critical to CD28 co-stimulation in maintaining T cell activation when CD28 has been down-regulated because of repeated stimulation. The 4-1BB signal synergized with CD28 co-stimulation by lowering the threshold of anti- CD28 required to sustain proliferation and IL-2 production. The 4-1BB signal also modulated CD28-mediated cytokine profiles by markedly enha ncing Th1 but suppressing Th2-type cytokine production. The 4-1BB sign al generated Th1-type cells, as identified by intracellular IFN-gamma production. IFN-gamma induction was detected preferentially in 4-1BB-e xpressing cells, but not in those expressing CD30. 4-1BB and CD30 were induced in both CD4(+) and CD8(+) cells, but the location of the two molecules was mutually exclusive in each T cell subset. Our study sugg ests that the 4-1BB signal regulates CD28 co-stimulation in the target ed subset cells to favor Th1 development and maintain long-term cell g rowth.