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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 (DCOVA) 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-Kb/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-XL 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. [ABSTRACT FROM AUTHOR]

Involvement of CD4+ helper T (Th) cells is crucial for CD8+ cytotoxic T lymphocyte (CTL)-mediated immunity. However, CD4+ Th’s signals that govern CTL survival and functional memory are still not completely understood. In this study, we assessed the role of CD4+ Th cells with acquired antigen-presenting machineries in determining CTL fates. We utilized an adoptive co-transfer into CD4+ T cell-sufficient or -deficient mice of OTI CTLs and OTII Th cells or Th cells with various gene deficiencies pre-stimulated in vitro by ovalbumin (OVA)-pulsed dendritic cell (DCova). CTL survival was kinetically assessed in these mice using FITC-anti-CD8 and PE-H-2Kb/OVA257-264 tetramer staining by flow cytometry. We show that by acting via endogenous CD40L and IL-2, and acquired peptide-MHC-I (pMHC-I) complex signaling, CD4+ Th cells enhance survival of transferred effector CTLs and their differentiation into the functional memory CTLs capable of protecting against highly-metastasizing tumor challenge. Moreover, RT-PCR, flow cytometry and Western blot analysis demonstrate that increased survival of CD4+ Th cell-helped CTLs is matched with enhanced Akt1/NF-κB activation, down-regulation of TRAIL, and altered expression profiles with up-regulation of prosurvival (Bcl-2) and down-regulation of proapoptotic (Bcl-10, Casp-3, Casp-4, Casp-7) molecules. Taken together, our results reveal a previously unexplored mechanistic role for CD4+ Th cells in programming CTL survival and memory recall responses. This knowledge could also aid in the development of efficient adoptive CTL cancer therapy. [ABSTRACT FROM AUTHOR]