title: Regulation of T cell activation and tolerance by phospholipase C gamma-1-dependent integrin avidity modulation.
abstract: Ag receptor engagement without costimulation induces a tolerant state in CD4(+) T cells termed anergy. Anergic CD4(+) T cells are primarily characterized by the inability to produce IL-2, but the biochemical basis for this functional defect is not completely understood. We demonstrate that primary CD4(+) T cells anergized by costimulatory blockade exhibit impaired TCR-coupled phospholipase C (PLC)gamma-1 activation. This defect is associated with the marked reduction of multiple downstream signaling events required for IL-2 transcription, including mobilization of intracellular Ca(2+) and activation of the mitogen-activated protein kinase cascade. We also found that primary anergic CD4(+) T cells fail entirely to modulate their integrin binding avidity in response to TCR stimulation. Integrin avidity modulation is required for full T cell activation and effector function, and as we show in this study, is completely dependent upon PLCgamma-1 activity. Finally, analogs that mimic the actions of diacylglycerol and inositol 1,4,5-triphosphate, the immediate products of PLCgamma-1 activity, restored integrin avidity modulation and IL-2 production by anergic T cells. Thus, deficient coupling of PLCgamma-1 to the TCR appears to be a central biochemical defect that could potentially account for the failure of multiple functional responses in primary anergic CD4(+) T cells.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Wells
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Liu
authors.forename: Brian
authors.initials: B
authors.lastname: Hondowicz
authors.forename: Jidong
authors.initials: J
authors.lastname: Zhang
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Freedman
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D016023:Integrins / Q000378:metabolism* / Q000502:physiology; D007399:Interphase / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D051966:Phospholipase C gamma; D011485:Protein Binding / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D010738:Type C Phospholipases / Q000502:physiology*
chemical_list: D016023:Integrins; D010738:Type C Phospholipases; D051966:Phospholipase C gamma