Disruption of CD154:CD40 blocks generation of allograft immunity without affecting APC activation

David M. Shepherd, Nancy I. Kerkvliet

Research output: Contribution to journalArticlepeer-review

Abstract

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, presumably by activated Th cells, leads to increased APC function as defined by up-regulation of costimulatory molecules and enhancement of IL-12 production. In this report, we directly examined the contribution of the CD154:CD40 pathway in a murine model of allograft rejection. Generation of both the CTL and alloantibody responses following injection with allogeneic P815 tumor cells was severely compromised in CD154 knockout mice and wild- type C57BL/6 mice treated with the anti-CD154 mAb, MR1. Splenic production of IL-2, IFN-γ, and TNF was significantly suppressed from CD154-deficient mice, indicating 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(-/-) mice with the agonistic anti-CD40 mAb, FGK45, generated activated APCs yet failed to restore either the CTL or alloantibody responses to P815. Likewise, immunization with B7-transfected P815 tumor cells failed to generate expansion of the CTL effector population in CD154(-/-) mice. These results suggest that the generation of allograft immunity is dependent on the interaction of CD154 with CD40 but not primarily for the activation of APCs.

Original languageEnglish
Pages (from-to)2470-2477
Number of pages8
JournalJournal of Immunology
Volume163
Issue number5
StatePublished - Sep 1 1999

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