title: Protein Tyrosine Phosphatase SHP-1 Modulates T Cell Responses by Controlling Cbl-b Degradation.
abstract: Previously, we demonstrated that CD28 and CTLA-4 signaling control Casitas-B-lineage lymphoma (Cbl)-b protein expression, which is critical for T cell activation and tolerance induction. However, the molecular mechanism(s) of this regulation remains to be elucidated. In this study, we found that Cbl-b fails to undergo tyrosine phosphorylation upon CD3 stimulation because SHP-1 is recruited to and dephosphorylates Cbl-b, whereas CD28 costimulation abrogates this interaction. In support of this finding, T cells lacking SHP-1 display heightened tyrosine phosphorylation and ubiquitination of Cbl-b upon TCR stimulation, which correlates with decreased levels of Cbl-b protein. The aberrant Th2 phenotype observed in T cell-specific Shp1(-/-) mice is reminiscent of heightened Th2 response in Cblb(-/-) mice. Indeed, overexpressing Cbl-b in T cell-specific Shp1(-/-) T cells not only inhibits heightened Th2 differentiation in vitro, but also Th2 responses and allergic airway inflammation in vivo. Therefore, SHP-1 regulates Cbl-b-mediated T cell responses by controlling its tyrosine phosphorylation and ubiquitination.
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China; Department of Nephrology, The First Affiliated Hospital, Guangzhou Medical University, 510120 Guangzhou, People's Republic of China;
authors.forename: Yun
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Section of Nephrology, Department of Medicine, The University of Chicago, Chicago, IL 60637; and.
authors.forename: Guilin
authors.initials: G
authors.lastname: Qiao
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China;
authors.forename: Juan
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China;
authors.forename: Rong
authors.initials: R
authors.lastname: Tang
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210;
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210;
authors.forename: Samantha
authors.initials: S
authors.lastname: Warwar
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia 6009, Australia.
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, People's Republic of China; jian.zhang@osumc.edu taolj@csu.edu.cn.
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; Section of Nephrology, Department of Medicine, The University of Chicago, Chicago, IL 60637; and jian.zhang@osumc.edu taolj@csu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000737:chemistry / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; C118387:Cblb protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6