Abstract
LFA-1 signaling is required for the generation of central memory CD8(+) T cells in priming phase. However, its role for effector and memory CD8(+) T cell survival in transition and maintenance phases is elusive. We transferred effector and memory CD8(+) T cells into C57BL/6 and CD54(-/-) mice, which were generated by cultivation of ovalbumin (OVA)-pulsed dendritic cells (DC(OVA)) with naïve CD8(+) T cells derived from transgenic OT I mice and purified from effector CD8(+) T cell-transferred C57BL/6 mice, respectively. We then assessed kinetics of T cell survival using PE-H2-K(b)/OVAI tetramer and FITC-CD8 staining by flow cytometry. We found that survival of transferred effector and memory CD8(+) T cells in CD54(-/-) mice significantly decreased (p<0.05) compared to that in C57BL/6 mice due to an increased T cell apoptosis, which is mediated via downregulation of proapoptotic Bid, anti-apoptotic Bcl-2, Bcl-X(L) and pro-Caspase-8, and up-regulation of apoptotic Bax and cleaved Caspase-3 and -7 by RNA array and Western blotting analyses. Decreased expression of CD27 and IL-15R on transferred CD8(+) T cells with less survival was found to be associated with increased T cell apoptosis, which was confirmed by silencing CD27 with siRNA transfection or using CD8(+) (IL-15R(-/-))T cells for adoptive transfer into C57BL/6 mice. These data indicate that LFA-1 signal defect-induced CD8(+) T cell apoptosis is associated with reduced CD27 costimulation and IL-15R survival signal. Therefore, our study provides important evidence on and elucidates the molecular mechanism associated with the role LFA-1 signaling plays in effector and memory CD8(+) T cell survival.