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CD8⁺ T lymphocyte apoptosis is regulated by protein O- glycosylation

  • Author(s): Van Dyken, Steven John
  • et al.
Abstract

Homeostasis is maintained after an immune response by apoptotic death of the majority of clonally expanded T cells. Evidence for the involvement of specific extracellular O-glycan modifications occurring during immune activation has previously emerged from analysis of CD8⁺ T cells deficient in ST3Gal-I, which express the activated O-glycan phenotype and undergo apoptosis in vivo in the absence of activation stimuli. The studies described in this dissertation further explore the influence of ST3Gal-I-mediated sialylation on CD8⁺ T cell apoptosis and the maintenance of homeostasis throughout immune responses produced in vitro and in vivo. To determine the effect of constitutive presence of ST3Gal-I on O-glycans production during immune activation, mice expressing an ST3Gal-I transgene in the T cell lineage were generated, characterized, and challenged with various immunologic stimuli. The specific involvement of potential mediators of CD8⁺ T cell apoptosis induced by ST3Gal-I deficiency was tested by analyzing double mutant mice. Finally, the mechanism of apoptosis was addressed by determining the involvement of intracellular signaling proteins Bcl-2 and Bim, which have been previously implicated in mediating CD8⁺ T cell apoptosis. These studies reveal novel mechanistic and structural features of apoptosis regulated by protein O-glycosylation, and a clear relationship to the post-immune contraction of CD8⁺ T cells. On wild-type CD8⁺ T cells, increased presence of unsialylated Core 1 O-glycans correlates with apoptosis and sensitizes them to in vitro apoptotic death induced by O-glycan crosslinking. Immune activation of ST3Gal-I transgenic CD8⁺ T cells reveals that unsialylated Core 1 O -glycans can be generated specifically on cells undergoing apoptotic death, by a post-transcriptional mechanism. This O-glycan-dependent CD8 T cell apoptosis does not act through CD43, Core 2 GlcNAcT-1-generated Core 2 O-glycan structures, or Galgt1-generated complex gangliosides. Furthermore, CD8⁺ T cell apoptosis mediated by O-glycans does not rely on Bcl-2 levels, and can attenuate the in vivo accumulation of CD8⁺ T cells normally induced by the absence of Bcl-2 family member Bim. Thus, these studies reveal novel mechanistic features of an essential physiologic mechanism of CD8⁺ T cell apoptosis that follows TCR stimulation and enables contraction upon immune signal attenuation

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