title: LFA-1 defect-induced effector/memory CD8+ T cell apoptosis is mediated via Bcl-2/Caspase pathways and associated with downregulation of CD27 and IL-15R.
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.
authors.affiliation: Research Unit, Saskatchewan Cancer Agency, Department of Oncology, College of Medicine, University of Saskatchewan, 20 Campus Drive, Saskatoon S7N 4H4, Canada.
authors.forename: Zhenmin
authors.initials: Z
authors.lastname: Ye
authors.forename: Meiqing
authors.initials: M
authors.lastname: Shi
authors.forename: Shulin
authors.initials: S
authors.lastname: Xu
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D007156:Immunologic Memory; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D053647:Receptors, Interleukin-15 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D053647:Receptors, Interleukin-15; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D018799:Intercellular Adhesion Molecule-1; D020169:Caspases