title: Posttranscriptional silencing of effector cytokine mRNA underlies the anergic phenotype of self-reactive T cells.
abstract: Self-reactive T cell clones that escape negative selection are either deleted or rendered functionally unresponsive (anergic), thus preventing them from propagating host tissue damage. By using an in vivo model, we investigated molecular mechanisms for T cell tolerance, finding that despite a characteristic inability to generate effector cytokine proteins, self-reactive T cells express large amounts of cytokine mRNAs. This disconnect between cytokine message and protein was not observed in T cells mounting productive responses to foreign antigens but, instead, was seen only in those responding to self, where the block in protein translation was shown to involve conserved AU-rich elements within cytokine 3'UTRs. These studies reveal that translation of abundant cytokine mRNAs is limited in self-reactive T cells and, thus, identify posttranscriptional silencing of antigen-driven gene expression as a key mechanism underlying the anergic phenotype of self-reactive T cells.
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Alejandro V
authors.initials: AV
authors.lastname: Villarino
authors.forename: Shoshana D
authors.initials: SD
authors.lastname: Katzman
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gallo
authors.forename: Omer
authors.initials: O
authors.lastname: Miller
authors.forename: Shuwei
authors.initials: S
authors.lastname: Jiang
authors.forename: Michael T
authors.initials: MT
authors.lastname: McManus
authors.forename: Abul K
authors.initials: AK
authors.lastname: Abbas
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D017635:Clonal Anergy; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007108:Immune Tolerance; D051379:Mice; D008822:Mice, Transgenic; D014176:Protein Biosynthesis / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D034743:RNA-Induced Silencing Complex / Q000276:immunology / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D001324:Autoantigens; D016207:Cytokines; D012333:RNA, Messenger; D034743:RNA-Induced Silencing Complex