CD40/CD154 interactions at the interface of tolerance and immunity

Annu Rev Immunol. 2004;22:307-28. doi: 10.1146/annurev.immunol.22.012703.104533.


Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present a hypothesis that alpha CD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of alpha CD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.

Publication types

  • Review

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • CD40 Antigens / immunology*
  • CD40 Antigens / metabolism
  • CD40 Ligand / immunology*
  • CD40 Ligand / metabolism
  • Cell Communication / immunology
  • Dendritic Cells / immunology
  • Humans
  • Immune Tolerance*
  • Lymphocyte Activation / immunology
  • Models, Immunological*
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology


  • CD40 Antigens
  • CD40 Ligand