title: Up-regulation of Cbl-b is associated with LSECtin-mediated inhibition of different CD4+ T-cell subsets.
abstract: Recently, LSECtin was identified as a co-inhibitory molecule involved in the control of T cell-mediated acute liver injury. However, it is not known whether LSECtin also suppresses the function of different CD4(+) T-cell subsets. In this study, we demonstrate that LSECtin-mediated signaling potently inhibits the proliferation and IL-2 production of total, naive and pre-activated CD4(+) T cells. However, exogenous IL-2 does not overcome the inhibitory effect on the proliferation of naive CD4(+) T cells. Based on the LSECtin-mediated inhibition of pre-activated CD4(+) T cells, we further analyzed the role of LSECtin in different effector CD4(+) T-cell subsets including Th1, Th2 and Th17. We observed that LSECtin significantly suppressed the production of their signature cytokines suggesting that LSECtin may also play an inhibitory role in the effector phase. LSECtin did not inhibit the CD4(+) T-cell proliferation induced by PMA (phorbol myristate acetate) and ionomycin suggesting that the LSECtin-mediated inhibition reduces the activation of the proximal TCR signalsome. The inhibition of CD4(+) T-cell activation mediated by LSECtin is associated with the up-regulation of Cbl-b and has no effect on GRAIL, Itch and SHP-2 phosphatase. Furthermore, LSECtin-initiated inhibition is compromised in Cbl-b mutant CD4(+) T cells. Taken together, these data demonstrate that LSECtin-mediated signaling up-regulates the threshold of CD4(+) T cell activation via tuning the expression of Cbl-b.
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Dianyuan
authors.initials: D
authors.lastname: Zhao
authors.forename: Mengyao
authors.initials: M
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Biao
authors.initials: B
authors.lastname: Liu
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Wang
authors.forename: Juntao
authors.initials: J
authors.lastname: Yang
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
authors.forename: Li
authors.initials: L
authors.lastname: Tang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000818:Animals; D061207:Calcium Ionophores / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D049109:Cell Proliferation; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D061207:Calcium Ionophores; D002273:Carcinogens; C118387:Cblb protein, mouse; D007376:Interleukin-2; C561095:LSECtin protein, mouse; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell; D011991:Receptors, Virus; D015759:Ionomycin; C471637:Itch protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D013755:Tetradecanoylphorbol Acetate