CD40 ligand expression abrogates infectious tolerance induced by apoptotic cells

Abstract

The decision to generate a productive immune response or tolerance after pathogenic insult often depends on the context in which T cells first encounter Ag. Ag encountered in the presence of apoptotic cells leads to immune tolerance, while the presence of necrotic cells promotes immunity. Using a classical system of tolerance induction, we re‐examined the tolerance induced by i.v. injection of apoptotic cells. In this system, cross‐presentation of Ag associated with apoptotic cells fails to prime CD4+ T cell‐mediated help and induces CD8+ suppressor T cells that mediate unresponsiveness. While apoptotic spleen cells induce immune tolerance when injected i.v., activation by PMA/ionomycin or anti‐CD3/CD28 mAb prior to apoptosis induction abrogated the ability to induce tolerance. Moreover, the activated apoptotic cells directly primed CD4+ T cells leading to immunity rather than tolerance. Further studies revealed a role for the costimulatory molecule CD40 ligand (CD40L), as tolerance resulted from i.v. injection of either naïve or activated apoptotic CD40L−/− cells and co‐injection of an agonistic anti‐CD40 mAb with naïve apoptotic cells induced robust immunity. In sum, these results show the key role of CD40L in determining the immune response to Ag in the presence of apoptotic cells, and suggest naïve apoptotic cells induce tolerance because CD8+ T cells fail to receive “help” via CD40‐CD40L binding.