SDF-1α Degrades whereas Glycoprotein 120 Upregulates Bcl-2 Interacting Mediator of Death Extralong Isoform: Implications for the Development of T Cell Memory

Abstract

After a primary immune response, T cell memory occurs when a subset of Ag-specific T cells resists peripheral selection by acquiring resistance to TCR-induced death. Recent data have implicated Bcl-2 interacting mediator of death (Bim) as an essential mediator of the contraction phase of T cell immunity. In this article, we describe that stromal-derived factor-1α (SDF-1α) ligation of CXCR4 on activated T cells promotes two parallel processes that favor survival, phospho-inactivation of Foxo3A, as well as Bim extralong isoform (BimEL) degradation, both in an Akt- and Erk-dependent manner. Activated primary CD4 T cells treated with SDF-1α therefore become resistant to the proapoptotic effects of TCR ligation or IL-2 deprivation and accumulate cells of a memory phenotype. Unlike SDF-1α, gp120 ligation of CXCR4 has the opposite effect because it causes p38-dependent BimEL upregulation. However, when activated CD4 T cells are treated with both gp120 and SDF-1α, the SDF-1α–driven effects of BimEL degradation and acquired resistance to TCR-induced death predominate. These results provide a novel causal link between SDF-1α–induced chemotaxis, degradation of BimEL, and the development of CD4 T cell memory.