CD28 can promote T cell survival through a phosphatidylinositol 3-kinase-independent mechanism

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Abstract
Phosphatidylinositol 3(Pl3)-kinase is implicated in various biological responses, including protection from apoptosis, although its role in antigen-induced T cell death and the molecular effectors it triggers remains ill-defined. Here, we investigated the role of Pl3-kinase activity in the prevention of T cell receptor/CD3-induced cell death by CD28. Pl3-kinase inhibitors blocked the up-regulation of Bcl-XL by CD28, without impairing the prevention of T cell receptor/CD3-triggered apoptosis by CD28, hence showing the existence of a cell-survival pathway independent of Pl3-kinase activity and up-regulation of Bcl-XL. Instead, we show that up-regulation of FasL which is instrumental in CD3-induced apoptosis was prevented upon CD28 co-stimulation. These results indicate that Pl3-kinase couples CD28 to Bcl-XL up-regulation and provide a molecular basis for the role of CD28 in cell survival through a Pl3-kinase-independent mechanism including FasL down-regulation.