CD28 COSTIMULATION PREVENTS CELL-DEATH DURING PRIMARY T-CELL ACTIVATION

CD28 has been demonstrated to play an important role in augmenting T c ell proliferation and effector function. Costimulation through CD28 ha s also been reported to enhance human T cell survival. In this report, we have further investigated the role of CD28 in regulating T cell su rvival by comparing the survival characteristics of T cells from wild- type and CD28-deficient mice. CD28 costimulation of anti-CD3-activated cells augmented the viability of T cells from wild-type but not from CD28-deficient mice. CTLA4Ig treatment reduced wild-type T cell viabil ity to a level comparable with CD28-deficient T cells. The ability of CD28 to enhance survival during T cell activation correlated positivel y with its ability to up-regulate the protein product of the cell surv ival gene bcl-x(L). No differences in the expression of either Bcl-2 o r Fas were observed between wild-type and CD28-deficient T cells. The CD28-dependent enhancement of cell survival during in vitro activation was found to be independent of Fas expression, as CD28 costimulation enhanced T cell survival to comparable levels in both wild-type and lp r animals. Cell death in CD28-deficient animals and in wild-type anima ls treated with CTLA4Ig displayed the morphologic characteristics of a poptosis. Additionally, inhibitors of ICE proteases could reverse cell death induced by TCR engagement in the absence of CD28 costimulation. Thus, CD28 costimulation not only enhances the proliferative expansio n of cells activated through the TCR but also increases the likelihood that individual cells survive during T cell activation.