Diverse transcriptional response of CD4+ T cells to stromal cell-derived factor SDF-1: cell survival promotion and priming effects of SDF-1 on CD4+ T cells.
Stromal cell-derived factor (SDF)-1 is a ligand for the chemokine receptor CXCR4 which is broadly expressed in lymphocytes, but the effects of SDF-1 on T cells are largely unknown. When examined using complementary DNA microarray, up-regulation of genes which are associated with DNA repair, detoxification, apoptosis, cell morphology, cell adhesion, and signal transduction was seen in CD4(+) T cells upon SDF-1 exposure. SDF-1 was shown to promote CD4(+) T cell survival through the phosphatidylinositol 3-kinase (PI3K)- and mitogen-activated protein kinase (MAPK)-cascades without cell cycle progression. The proapoptotic Bcl-2 antagonistic of cell death protein was also seen inactivated by the SDF-1-mediated activation of MAPK-extracellular signal-regulated kinases (MEK)-extracellular signal-regulated kinase-ribosomal S6 kinases- and PI3K-pathways. Moreover, the genes known to be associated with cell survival were up-regulated upon SDF-1 exposure and were linked to the MAPK-MEK and PI3K-pathways. Thus, SDF-1 promotes cell survival by two mechanisms: posttranslational inactivation of the cell death machinery and an increased transcription of cell survival-related genes. SDF-1 also primed resting CD4(+) T cells for cytokine- and TCR-mediated stimuli. These data suggest that the SDF-1-mediated cell survival combined with its priming function would set T cells to respond to immunologic challenges.
Suzuki
Y
Y
Experimental Retrovirology Section, Center for Cancer Research and HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Rahman
M
M
Mitsuya
H
H
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000502:physiology*; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D019743:Chemokines, CXC / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology*; D051025:bcl-Associated Death Protein
C494819:BAD protein, human; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; D004791:Enzyme Inhibitors; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D019718:Receptors, CXCR4; D051025:bcl-Associated Death Protein