Dm. Shepherd et Ni. Kerkvliet, Disruption of CD154 : CD40 blocks generation of allograft immunity withoutaffecting APC activation, J IMMUNOL, 163(5), 1999, pp. 2470-2477
CD154 (CD40 ligand, gp39) interaction with Its receptor CD40 has been shown
to be critically important for the generation of cell-mediated as well as
humoral immunity, It has been proposed that ligation of CD40 on APCs, presu
mably by activated Th cells, leads to increased APC function as defined by
up-regulation of costimulatory molecules and enhancement of IL-12 productio
n. In this report, we directly examined the contribution of the CD154:CD40
pathway in a murine model of allograft rejection. Generation of both the CT
L and alloantibody responses following injection with allogeneic P815 tumor
cells was severely compromised in CD154 knockout mice and wad-type C57BL/6
mice treated with the anti-CD154 mAb, MR1, Splenic production of IL-2 IFN-
gamma, and TNF was significantly suppressed from CD154-deficient mice indic
ating a lack of T cell priming. However, splenic cells from CD154 knockout
mice induced comparable levels of CD86 expression and IL-12 production when
compared with their wild-type littermates. The treatment of CD154(-/-) mic
e with the agonistic anti-CD40 mAb, FGK45, generated activated APCs yet fai
led to restore either the CTL or alloantibody responses to P815, Likewise,
immunization with B7-transfected P815 tumor cells failed to generate expans
ion of the CTL effector population in CD154(-/-) mice. These results sugges
t that the generation of allograft immunity is dependent on the interaction
of CD154 with CD40 but not primarily for the activation of APCs.