CD40/CD154 interactions at the interface of tolerance and immunity

Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, Randolph J. Noelle

Research output: Contribution to journalReview articlepeer-review

586 Scopus citations


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 αCD154 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 αCD154-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.

Original languageEnglish (US)
Pages (from-to)307-328
Number of pages22
JournalAnnual review of immunology
StatePublished - 2004
Externally publishedYes


  • Cell-mediated immunity
  • Donor transfusion
  • Immature dendritic cell
  • Suppressor
  • Transplantation tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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