title: Distinct contributions of CD4+ T cell subsets in hepatic ischemia/reperfusion injury.
abstract: Helper T cells are known to mediate hepatic ischemia/reperfusion (I/R) injury. However, the precise mechanisms and subsets of CD4(+) T cells that contribute to this injury are still controversial. Therefore, we sought to determine the contributions of different CD4(+) T cell subsets during hepatic I/R injury. Wild-type, OT-II, or T cell receptor (TCR)-delta-deficient mice were subjected to 90 min of partial hepatic ischemia followed by 8 h of reperfusion. Additionally, wild-type mice were pretreated with anti-CD1d, -NK1.1, or -IL-2R-alpha antibodies before I/R injury. OT-II mice had diminished liver injury compared with wild-type mice, implicating that antigen-dependent activation of CD4(+) T cells through TCRs is involved in hepatic I/R injury. TCR-delta knockout mice had decreased hepatic neutrophil accumulation, suggesting that gammadelta T cells regulate neutrophil recruitment. We found that natural killer T (NKT) cells, but not NK cells, contribute to hepatic I/R injury via CD1d-dependent activation of their TCRs, as depletion of NKT cells by anti-CD1d antibody or depletion of both NKT cells and NK cells by anti-NK1.1 attenuated liver injury. Although regulatory T cells (Treg) are known to suppress T cell-dependent inflammation, depletion of Treg cells had little effect on hepatic I/R injury. The data suggest that antigen-dependent activation of CD4(+) T cells contributes to hepatic I/R injury. Among the subsets of CD4(+) T cells, it appears that gammadelta T cells contribute to neutrophil recruitment and that NKT cells directly injure the liver. In contrast, NK cells and Treg have little effects on hepatic I/R injury.
authors.affiliation: The Laboratory of Trauma, Sepsis and Inflammation Research, Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuboki
authors.forename: Nozomu
authors.initials: N
authors.lastname: Sakai
authors.forename: Johannes
authors.initials: J
authors.lastname: Tschöp
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Edwards
authors.forename: Alex B
authors.initials: AB
authors.lastname: Lentsch
authors.forename: Charles C
authors.initials: CC
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D019676:Genes, T-Cell Receptor delta; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008107:Liver Diseases / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000276:immunology*; D020556:Neutrophil Infiltration; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology
chemical_list: D055610:Antigens, CD1d; D000950:Antigens, Ly; C526879:Cd1d1 protein, mouse; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; C527211:Klrb1c protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B; D016692:Receptors, Antigen, T-Cell, gamma-delta