title: Ectopic B-Raf expression enhances extracellular signal-regulated kinase (ERK) signaling in T cells and prevents antigen-presenting cell-induced anergy.
abstract: T cells that receive stimulation through the T cell receptor (TCR) in the absence of costimulation become anergic and are refractory to subsequent costimulation. This unresponsiveness is associated with the constitutive activation of the small G protein, Rap1, and the lack of Ras-dependent activation of ERK. Recent studies suggest that Rap1 can activate the MAP kinase kinase kinase B-Raf that is either endogenously or ectopically expressed. Peripheral T cells generally do not express B-Raf; therefore, to test the hypothesis that ectopic expression of B-Raf could permit Rap1 to activate ERK signaling, we generated transgenic mice expressing B-Raf within peripheral T cells. This converted Rap1 into an activator of ERK, to enhance ERK activation and proliferation following TCR engagement in the absence of costimulation. When T cells were incubated with engineered APCs presenting antigen on I-Ek and expressing low levels of B7, they became anergic, displayed constitutive activation of Rap1, and were deficient in Ras and ERK activation. However, when incubated with the same APCs, T cells expressing the B-Raf transgene proliferated upon restimulation and displayed elevated ERK activation. Thus B-Raf expression and enhanced ERK activation is sufficient to prevent anergy in a model of APC-induced T cell anergy. However, studies using anti-TCR antibody-induced anergy showed that the ability of ERKs to reverse T cell anergy is dependent on the anergic model utilized.
authors.affiliation: Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97239, USA.
authors.forename: Tara J
authors.initials: TJ
authors.lastname: Dillon
authors.forename: Vladamir
authors.initials: V
authors.lastname: Karpitski
authors.forename: Scott A
authors.initials: SA
authors.lastname: Wetzel
authors.forename: David C
authors.initials: DC
authors.lastname: Parker
authors.forename: Andréy S
authors.initials: AS
authors.lastname: Shaw
authors.forename: Philip J S
authors.initials: PJ
authors.lastname: Stork
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D015153:Blotting, Western; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D037181:Lectins, C-Type; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000096:biosynthesis* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D014018:Tissue Distribution; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D004268:DNA-Binding Proteins; D037181:Lectins, C-Type; D020928:Mitogen-Activated Protein Kinases; D010455:Peptides; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D020827:rap1 GTP-Binding Proteins; D000099192:CD69 Antigens; C482120:Braf protein, mouse