POTENTIAL ROLE OF 4-1BB IN T-CELL ACTIVATION - COMPARISON WITH THE COSTIMULATORY MOLECULE CD28

The expression of the murine T cell Ag 4-1BB, a member of the TNF-R fa mily, is induced by T cell activation, Previously, we and others had s hown that signaling through 4-1BB enhanced proliferative T cell respon ses, To investigate a potential role for the interaction of 4-1BB with its ligand (4-1BBL) in T cell activation, we studied the ability of a soluble chimera of 4-1BB (4-1BBFc) to interfere with proliferative re sponses and cytokine production in models of activation dependent in i ntercellular interactions. The potential blocking effect of 4-1BBFc wa s compared with that of the chimeric molecule CTLA-4lg, a reagent know n to interfere with the interaction of CD28 (and/or CTLA-4) with B7 co stimulatory receptors, In this study, we report that 4-1BBFc partially blocked both the activation of unfractionated splenocytes triggered b y soluble anti-CD3 (anti-CD3s), and the more physiologically relevant responses to alloantigen. In addition, we show that both chimeric mole cules partially blocked proliferative responses and IL-2 secretion by highly purified resting T cells activated with anti-CD3s in the presen ce of fixed accessory cells that express B7 receptors and 4-1BBL, Furt hermore, in this model system, the blocking capacity of 4-1BBFc and CT LA-4lg appears to correlate with the relative expression of their resp ective cognate receptors (4-1BBL and B7) on the accessory cell, Simult aneous addition of both blocking reagents produced an additive effect in the model systems studied.