Degranulation plays an essential part in regulating cell surface expression of Fas ligand in T cells and natural killer cells.
Fas ligand (FasL) triggers apoptosis during cytotoxicity mediated by cytotoxic T lymphocytes and during immune downregulation. The ability of T cells and natural killer cells to trigger apoptosis through this mechanism is controlled by the cell surface expression of FasL (ref. 2). Because FasL expression is up-regulated on activation, FasL was thought to be delivered directly to the cell surface. Here we show that newly synthesized FasL is stored in specialized secretory lysosomes in both CD4+ and CD8+ T cells and natural killer cells, and that polarized degranulation controls the delivery of FasL to the cell surface. In this way, FasL-mediated apoptosis is finely controlled by receptor-mediated target-cell recognition. The cytoplasmic tail of FasL contains signals that sort FasL to secretory lysosomes in hemopoietic cells. This pathway may provide a general mechanism for controlling the cell surface appearance of proteins involved in immune regulation.
Bossi
G
G
Sir William Dunn School of Pathology, University of Oxford.
Griffiths
G M
GM
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000378:metabolism*; D002402:Cathepsin D / Q000032:analysis; D015550:Cell Degranulation; D002458:Cell Fractionation; D002460:Cell Line; D053222:Fas Ligand Protein; D015870:Gene Expression; D053804:Granzymes; D006367:HeLa Cells; D006801:Humans; D007694:Killer Cells, Natural / Q000737:chemistry / Q000378:metabolism*; D037181:Lectins, C-Type; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D054353:Perforin; D010980:Platelet Membrane Glycoproteins / Q000032:analysis; D052899:Pore Forming Cytotoxic Proteins; D051381:Rats; D012697:Serine Endopeptidases / Q000032:analysis; D060149:Tetraspanin 30; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002402:Cathepsin D; D053222:Fas Ligand Protein; D053804:Granzymes; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D054353:Perforin; D010980:Platelet Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases; D060149:Tetraspanin 30; D000099192:CD69 Antigens; C554586:CD63 protein, human; C554587:Cd63 protein, mouse; C554588:Cd63 protein, rat; C505661:FASLG protein, human; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; C509212:GZMA protein, human