Lipid raft heterogeneity in human peripheral blood T lymphoblasts: a mechanism for regulating the initiation of TCR signal transduction.
Lateral mobility and spatial organization of proteins within the plasma membrane are likely to mediate the initial events coordinating T cell activation. Lipid rafts, distinct cholesterol/sphingolipid-rich membrane microdomains, provide a mechanism for this regulation by concentrating or excluding signaling proteins. We demonstrate in peripheral blood T cell lymphoblasts that immediate early phosphotyrosine signal transduction through the TCR complex is functionally dependent on a distinct population of lipid rafts. Specifically, cholesterol extraction destabilizes the membrane microdomains containing Lck, while the rafts containing the adapter protein linker for activation of T cells remain intact. Heterogeneity in the partitioning of these proteins in resting cells was confirmed by immunoelectron microscopy. After T cell activation, both Lck and the linker for activation of T cells colocalize to 50-100 nm microdomains in the plasma membrane, indicating that sequestration of these proteins into distinct lipid rafts may function to regulate the initiation of T cell signal transduction.
Schade
Andrew E
AE
Department of Pathology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Levine
Alan D
AD
D048868:Adaptor Proteins, Signal Transducing; D001769:Blood / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis; D002352:Carrier Proteins / Q000032:analysis; D002478:Cells, Cultured; D002784:Cholesterol / Q000737:chemistry; D003505:Cyclodextrins / Q000494:pharmacology; D006801:Humans; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000032:analysis / Q000378:metabolism; D021962:Membrane Microdomains / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000032:analysis; D010750:Phosphoproteins / Q000032:analysis; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure; D051746:ZAP-70 Protein-Tyrosine Kinase; D047392:beta-Cyclodextrins
D048868:Adaptor Proteins, Signal Transducing; D015704:CD4 Antigens; D002352:Carrier Proteins; D003505:Cyclodextrins; C110810:LAT protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D019000:Phosphotyrosine; D002784:Cholesterol; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human