Structural and mechanistic features of protein O glycosylation linked to CD8+ T-cell apoptosis.
CD8+ T-cell apoptosis is essential for the contraction phase of the immune response, yet the initiating signals and precise pathways involved are unresolved. The ST3Gal-I sialyltransferase is a candidate mechanistic component and catalyzes sialic acid addition to core 1 O-glycans during protein O glycosylation. ST3Gal-I inactivation or enzymatic removal of its product renders CD8+ T cells, but not CD4+ T cells, susceptible to apoptosis by differential cross-linking of O-glycoproteins in the absence of interleukin-2 and T-cell receptor (TCR) signaling. This results in caspase activation, DNA fragmentation, and phosphatidylserine externalization prior to cell death. We further show that ST3Gal-I function is regulated by a posttranscriptional mechanism operating distal to Golgi core 2 O glycosylation and is invariably linked to CD8+ T-cell contraction following viral (lymphocytic choriomeningitis virus) infection and bacterial (staphylococcal enterotoxin B) antigen immunization. The mechanism does not involve the ST3Gal-I substrate CD43 or core 2 O-glycan induction and overcomes the ability of Bcl-2 to inhibit the contraction phase in vivo. Loss of ST3Gal-I function further reduces Bim-deficient CD8+ T-cell accumulation without diminishing apoptotic sensitivity. We propose that an endogenous lectin activates an apoptotic pathway constructed in CD8+ T cells following TCR stimulation and enables contraction upon attenuation of immune signaling.
Van Dyken
Steven J
SJ
Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0625, USA.
Green
Ryan S
RS
Marth
Jamey D
JD
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000942:Antigens, Bacterial / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D002451:Cell Compartmentation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004768:Enterotoxins / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007109:Immunity / Q000187:drug effects / Q000276:immunology; D007970:Leukopenia / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry; D046188:Protein Modification, Translational / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism; D012799:Sialyltransferases / Q000737:chemistry* / Q000172:deficiency / Q000378:metabolism*; D013329:Structure-Activity Relationship; D019076:Transgenes; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
D017304:Annexin A5; D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D003432:Cross-Linking Reagents; D004768:Enterotoxins; D008565:Membrane Proteins; D011134:Polysaccharides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C031818:enterotoxin B, staphylococcal; D012799:Sialyltransferases; D019158:N-Acetylneuraminic Acid; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase