title: The molecular signature of CD8+ T cells undergoing deletional tolerance.
abstract: Peripheral tolerance induction is critical for the maintenance of self-tolerance and can be mediated by immunoregulatory T cells or by direct induction of T-cell anergy or deletion. Although the molecular processes underlying anergy have been extensively studied, little is known about the molecular basis for peripheral T-cell deletion. Here, we determined the gene expression signature of peripheral CD8(+) T cells undergoing deletional tolerance, relative to those undergoing immunogenic priming or lymphopenia-induced proliferation. From these data, we report the first detailed molecular signature of cells undergoing deletion. Consistent with defective cytolysis, these cells exhibited deficiencies in granzyme up-regulation. Furthermore, they showed antigen-driven Bcl-2 down-regulation and early up-regulation of the proapoptotic protein Bim, consistent with the requirement of this BH3-only protein for peripheral T-cell deletion. Bim up-regulation was paralleled by defective interleukin-7 receptor alpha (IL-7Ralpha) chain reexpression, suggesting that Bim-dependent death may be triggered by loss of IL-7/IL-7R signaling. Finally, we observed parallels in molecular signatures between deletion and anergy, suggesting that these tolerance pathways may not be as molecularly distinct as previously surmised.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Parish
authors.forename: Sudha
authors.initials: S
authors.lastname: Rao
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Torsten
authors.initials: T
authors.lastname: Juelich
authors.forename: Gareth S
authors.initials: GS
authors.lastname: Denyer
authors.forename: Gayle M
authors.initials: GM
authors.lastname: Davey
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: William R
authors.initials: WR
authors.lastname: Heath
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015415:Biomarkers / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D053804:Granzymes / Q000378:metabolism; D018398:Homeodomain Proteins / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D015415:Biomarkers; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; C064658:RAG-1 protein; D053804:Granzymes