CD40 PREFERENTIALLY COSTIMULATES ACTIVATION OF CD4(+) T-LYMPHOCYTES

CD40 is a membrane differentiation antigen constitutively expressed on B cells that induces B cell growth and Ig synthesis after ligation with anti-CD40 mAb or with the recently identified CD40 ligand (CD40L). CD40L is rapidly induced on T cells after activation with anti-CD3 mAb or mitogens. While CD40-CD40L interactions are clearly beneficial to B cells, we speculated that a reciprocal costimulation of T cells might also occur. We have used genetic transfection to demonstrate that interactions between human small, resting T cells and CD40(+) murine transfectants substantially augmented anti-CD3 induced T cell proliferation and resulted in the generation of CTL. T cell proliferation costimulated by CD40 was IL-2 dependent. The ability of CD40(+) transfectants to costimulate T cell proliferation was specific in that VCAM-1(+), CD54(+), CD72(+), CD56(+), CD31(+), and fas(+) transfectants in the same host cells were inactive. CD4(+) T cells preferentially responded to CD40 costimulation, whereas CD8(+) T cells were substantially less reactive. By contrast, costimulation with B7 transfectants induced equivalent proliferation in the CD4(+) and CD8(+) T cell subsets. in addition, adult naive and memory T cells, as well as cord blood T cells, were responsive to CD40. These findings suggest that the CD40-CD40L costimulation pathway may allow for selective expansion of CD4(+) T cells after interaction with CD40-bearing APC. The relatively restricted expression of CD40 on APC, as well as on medullary and cortical thymic epithelium, indicates a possible role for this interaction in T cell differentiation and activation.