title: Essential Roles of TIM-1 and TIM-4 Homologs in Adaptive Humoral Immunity in a Zebrafish Model.
abstract: TIM-1 and TIM-4 proteins have become increasingly attractive for their critical functions in immune modulation, particularly in CD4(+) Th2 cell activation. Thus, these proteins were hypothesized to regulate adaptive humoral immunity. However, further evidence is needed to validate this hypothesis. This study describes the molecular and functional characteristics of TIM-1 and TIM-4 homologs from a zebrafish (Danio rerio) model (D. rerio TIM [DrTIM]-1 and DrTIM-4). DrTIM-1 and DrTIM-4 were predominantly expressed in CD4(+) T cells and MHC class II(+) APCs under the induction of Ag stimulation. Blockade or knockdown of both DrTIM-1 and DrTIM-4 significantly decreased Ag-specific CD4(+) T cell activation, B cell proliferation, Ab production, and vaccinated immunoprotection against bacterial infection. This result suggests that DrTIM-1 and DrTIM-4 serve as costimulatory molecules required for the full activation of adaptive humoral immunity. DrTIM-1 was detected to be a trafficking protein located in the cytoplasm of CD4(+) T cells. It can translocate onto the cell surface under stimulation by TIM-4-expressing APCs, which might be a precise regulatory strategy for CD4(+) T cells to avoid self-activation before APCs stimulation. Furthermore, a unique alternatively spliced soluble DrTIM-4 variant was identified to exert a negative regulatory effect on the proliferation of CD4(+) T cells. The above findings highlight a novel costimulatory mechanism underlying adaptive immunity. This study enriches the current knowledge on TIM-mediated immunity and provides a cross-species understanding of the evolutionary history of costimulatory systems throughout vertebrate evolution.
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and.
authors.forename: Xiao-Gang
authors.initials: XG
authors.lastname: Xu
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and.
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Hu
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and.
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Ma
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and.
authors.forename: Li
authors.initials: L
authors.lastname: Nie
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and.
authors.forename: Tong
authors.initials: T
authors.lastname: Shao
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and shaojz@zju.edu.cn xianglx@zju.edu.cn.
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Xiang
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, People's Republic of China shaojz@zju.edu.cn xianglx@zju.edu.cn.
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Shao
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D000072596:Hepatitis A Virus Cellular Receptor 1; D056724:Immunity, Humoral / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000276:immunology*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D015027:Zebrafish / Q000276:immunology*; D029961:Zebrafish Proteins / Q000276:immunology*
chemical_list: D000072596:Hepatitis A Virus Cellular Receptor 1; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D029961:Zebrafish Proteins; C000601658:havcr1 protein, zebrafish