Enhanced response of T lymphocytes from Pgap3 knockout mouse: Insight into roles of fatty acid remodeling of GPI anchored proteins.
Glycosylphosphatidylinositol (GPI) is a complex glycolipid that serves as a membrane anchor for many cell-surface proteins, such as Thy-1 and CD48. GPI-anchored proteins (GPI-APs) play important roles in many biological processes, such as signal transduction and cell-cell interaction, through their association with lipid rafts. Fatty acid remodeling of GPI-APs in the Golgi apparatus is required for their efficient association with lipid rafts, i.e., the unsaturated fatty acid at the sn-2 position of the PI moiety is exchanged for the saturated fatty acid by PGAP2 and PGAP3. To investigate the immunological role of the fatty acid remodeling of GPI-APs, we generated a Pgap3 knockout mouse. In this mouse, GPI-APs are expressed on the cell surface without fatty acid remodeling, and fail to associate with lipid rafts. Male Pgap3 knockout mice were born alive at a ratio lower than expected from Mendel's law, whereas the number of female mice followed Mendel's law. All mice exhibited growth retardation and abnormal reflexes such as limb grasping. We focused T cell function in these mice and found that T cell development in the absence of Pgap3 was normal. However, the response of T cells was enhanced in Pgap3 knockout mice in both in vitro and in vivo studies, including alloreactive response, antigen-specific immune response, and experimental autoimmune encephalomyelitis. Cross-linking of Thy-1 in wild-type cells inhibited the signal transduced by the T cell receptor (TCR), whereas cross-linking of Thy-1 in Pgap3 knockout cells enhanced the TCR signal. These results suggest that GPI-APs localized in lipid rafts may modulate signaling through the TCR.
Department of Immunoregulation, Research Institute for Microbial Diseases, Laboratory of Immunoglycobiology, WPI Immunology Frontier Research Center, Japan. yoshiko@biken.osaka-u.ac.jp
Hidekazu
H
Murakami
Yetao
Y
Wang
Hidetoshi
H
Hasuwa
Yusuke
Y
Maeda
Taroh
T
Kinoshita
Yoshiko
Y
Murakami
D000818:Animals; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005227:Fatty Acids / Q000276:immunology*; D005260:Female; D017261:Glycosylphosphatidylinositols / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics*; D008297:Male; D021962:Membrane Microdomains / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018800:Thy-1 Antigens / Q000276:immunology*
D000941:Antigens; D005227:Fatty Acids; D017261:Glycosylphosphatidylinositols; D011948:Receptors, Antigen, T-Cell; D018800:Thy-1 Antigens; D002265:Carboxylic Ester Hydrolases; C571153:PGAP3 protein, mouse