Cutting edge: distinct TCR- and CD28-derived signals regulate CD95L, Bcl-xL, and the survival of primary T cells

Abstract

TCR-driven clonal expansion of T cells is limited by activation-induced cell death through CD95/CD95L interactions. This cell-contact dependent mechanism is attenuated by costimulation through CD28. Here, we show that primary rat lymph node T cells activated by "superagonistic" CD28-specific mAb, which do not require TCR-engagement for full T cell activation, do not up-regulate CD95L. CD28 superagonist activated T cells are highly resistant to artificial CD95 cross-linking, and display a marked up-regulation of the survival factor Bcl-x(L). Consistently, NF-kappaB factors, known to promote Bcl-x(L) transcription, are strongly activated by superagonistic CD28 mAb stimulation. In contrast, a weaker induction of NFAT, which positively regulates the CD95L gene, in CD28 activated cells as compared with TCR- or TCR/CD28-stimulated cells was observed. Thus, by recruiting the mitogenic activity of CD28 in the absence of TCR engagement, the anti-apoptotic signals provided by costimulation are revealed without interfering proapoptotic effects induced by TCR stimulation.