title: Blockade of the T cell immunoglobulin and mucin domain protein 3 pathway exacerbates sepsis-induced immune deviation and immunosuppression.
abstract: Sepsis is a life-threatening condition, but the pathophysiological basis and biomarkers for the monitoring of sepsis and as targets for therapy remain to be determined. We have shown previously that T cell immunoglobulin and mucin domain protein 3 (Tim-3), a negative immune regulator, is involved in the physiopathology of sepsis, but the underlying mechanisms remain unclear. In the present study, we showed that Tim-3 signalling modulated the response patterns of both macrophages and T helper cells in sepsis. Blockade of the Tim-3 pathway exacerbated sepsis-induced proinflammatory macrophage responses and lymphocyte apoptosis during the early phase of sepsis, and enhanced the shift to anti-inflammatory responses for both macrophages and T helper cells during the late phase of sepsis. Tim-3 signalling was found to regulate CD80 and CD86 expression on macrophages both in vivo and in vitro. Co-culture of T cells with Tim-3 knock-down macrophages led to a biased T helper type 2 (Th2) response, partially explaining how Tim-3 signalling shapes inflammation patterns in vivo. Further studies on this pathway might shed new light on the pathogenesis of sepsis and suggest new approaches for intervention.
authors.affiliation: Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences, Beijing, China; Institute of Immunology, Medical School of Henan University, Kaifeng, China; Department of Pathology, Zhengzhou People's Hospital, YIHE Hospital, Zhengzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.forename: C
authors.initials: C
authors.lastname: Kang
authors.forename: Y
authors.initials: Y
authors.lastname: Xiao
authors.forename: C
authors.initials: C
authors.lastname: Hou
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Xiao
authors.forename: T
authors.initials: T
authors.lastname: Zhou
authors.forename: Z
authors.initials: Z
authors.lastname: Wen
authors.forename: J
authors.initials: J
authors.lastname: Feng
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.forename: B
authors.initials: B
authors.lastname: Shen
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: G
authors.initials: G
authors.lastname: Han
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D016130:Immunophenotyping; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D015398:Signal Transduction / Q000187:drug effects; D057127:Single-Chain Antibodies / Q000494:pharmacology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies
keywords: T helper cell; Tim-3; macrophage; sepsis