title: T cell activation threshold regulated by E3 ubiquitin ligase Cbl-b determines fate of inducible regulatory T cells.
abstract: E3 ubiquitin ligase Casitas-B-lineage lymphoma protein-b (Cbl-b) is critical for establishing the threshold for T cell activation and is essential for induction of T cell anergy. Recent studies suggest that Cbl-b is involved in the development of CD4(+)CD25(+) inducible regulatory T cells (iTregs). In this study, we report that the optimal induction of Foxp3 by naive CD4(+)CD25(-) T cells requires suboptimal TCR triggering. In the absence of Cbl-b, the TCR strength for optimal Foxp3 induction is downregulated in vitro. Using TCR-transgenic Rag(-/-) mice in combination with Cbl-b deficiency, we show that in vivo iTreg development is also controlled by Cbl-b via tuning the TCR strength. Furthermore, we show that Akt-2 but not Akt-1 regulates Foxp3 expression downstream of Cbl-b. Therefore, we demonstrate that Cbl-b regulates the fate of iTregs via controlling the threshold for T cell activation.
authors.affiliation: Section of Nephrology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. gqiao@bsd.uchicago.edu
authors.forename: Guilin
authors.initials: G
authors.lastname: Qiao
authors.forename: Yixia
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Li
authors.forename: Peter Q
authors.initials: PQ
authors.lastname: Tang
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
authors.forename: Tianlan
authors.initials: T
authors.lastname: Yang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015704:CD4 Antigens; C118387:Cblb protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; D053645:Interleukin-2 Receptor alpha Subunit; D016328:NF-kappa B; C064658:RAG-1 protein; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt