CD154 inhibits death of T cells via a Cis interaction with the [alpha]5[beta]1 integrin

CD154 plays a major role in the pathogenesis of several autoimmune and inflammatory diseases. In addition to CD40, soluble CD154 (sCD154) binds to other receptors namely [alpha]IIb[beta]3, [alpha]M[beta]2, [alpha]5[beta]1 and [alpha]v[beta]3 integrins. We have previously reported that binding of sCD154 to [alpha]5[beta]1 integrin expressed on several human T cell lines is capable of inhibiting Fas-induced cell death. In the current study, we show that such effect of the sCD154/[alpha]5[beta]1 interaction is not restricted to the cell death response induced by Fas but could also be exhibited toward other death signals such as TRAIL and TNF- [alpha]. We also demonstrate that sCD154 is capable of inhibiting Fas-mediated death of human activated T cells, more importantly of CD4.sup.+ than CD8.sup.+ T ones. Our data also show that membrane-bound CD154 and [alpha]5[beta]1 integrin expressed on the surface of distinct cells failed to influence cell death responses. However, when membrane-bound CD154 and [alpha]5[beta]1 are expressed on the surface of same cell, their interaction was capable of down regulating cell death. CD154 was shown to co-localize with the [alpha]5[beta]1 integrin on the surface of these cells. These data strongly suggest a cis-type of interaction between CD154 and [alpha]5[beta]1 when both are expressed on the same cell surface, rather than a trans-interaction which usually implicates the ligand and its receptor each expressed on the surface of a distinct cell. Taken together, these findings add to the list of roles through which CD154 is contributing to the pathogenesis of autoimmune-inflammatory diseases, i.e. by protecting T cells from death and enhancing their survival.