The roles of CD28 and CD40 ligand in T cell activation and tolerance

Costimulation of T cell activation involves both the B7:CD28 as well as the CD40 ligand (CD40L):CD40 pathway. To determine the importance of these pat hways to in vitro and in vivo T cell activation, a direct comparison was ma de of the responses of TCR transgenic T cells lacking either CD28 or CD40L, In vitro, CD28(-/-) T cells showed a greater reduction in proliferative re sponses to Ag than did CD40L(-/-) T cells, The absence of CD28 resulted in defective Th2 responses, whereas CD40L(-/-) T cells were defective in Th1 d evelopment. In vivo, CD28(-/-) T cells failed to expand upon immunization, whereas CD40L(-/-) T cells could not sustain a response. These results sugg est that CD28 is critical for initiating T cell responses, whereas CD40L is required for sustained Th1 responses, The different functional roles of th ese costimulatory pathways may explain why blocking B7:CD28 and CD40L:CD40 interactions has an additive effect in inhibiting T cell responses.