The role of a glycosyltransferase, ST6Gal I in regulating viral specific T and B cell responses

• Main Author: Zeng, Junwei
• Format: Others
• Published: Trace: Tennessee Research and Creative Exchange 2011
• Subjects: Glycosyltransferase; ST6Gal I; B cell; T cell; IgA; Immunity
• Online Access: http://trace.tennessee.edu/utk_graddiss/1244

Glycosylation is one of the most abundant post-translational modifications of proteins. Glycoproteins participate in virtually all aspects of cellular functions. ST6Gal I is a glycosyltransferase highly expressed by B and T cells. Here, we interrogated the role of ST6Gal I in viral specific B and T cell immune responses, as well as examined how loss of this enzyme impacted viral pathogenesis. First, to understand how loss of ST6Gal I expression impacted viral specific humoral responses, we infected ST6Gal I-/- mice with influenza virus. We discovered that loss of ST6Gal I expression results in both reduced influenza specific antibodies levels and decreased viral-specific antibody secreting cells numbers. Following influenza infection, mice that received ST6Gal I-/- B cells showed reduced influenza-specific IgM responses compared to mice that received wild-type B cells. These experiments demonstrated that the expression of ST6Gal I by B cells is required for optimal viral-specific humoral response. We further examined how loss of ST6Gal I expression impacted the anti-influenza IgA response. We observed that immune ST6Gal I-/- mice displayed higher viral specific IgA levels and altered sialylation of IgG and IgA, which have been implicated in a human disease, IgA nephropathy. Moreover, ST6Gal I-/- mice exhibited increased immunoglobulin deposition in kidney glomeruli following influenza infection. These data suggest that ST6Gal I deficiency, together with influenza infection, may result in the initiation of a kidney disease. Finally, we examined how ST6Gal I expression regulated CD8 T cell responses. We discovered that ST6Gal I is differentially expressed during CD8 T cell activation. To understand its relevance, we infected ST6Gal I-/- mice and demonstrated that the early expansion of effector T cells was impaired in a cell intrinsic manner. Moreover, in the absence of ST6Gal I, the differentiation of CD8 T cells skewed towards memory precursor cells, whereas terminal effector cell expansion was impaired. Mechanistically, we identified delayed surface expression of IL-2Ralpha on ST6Gal I-/- CD8 T cells due to impaired IL-2/IL-2R signaling. These studies implicate that ST6Gal I expression enhances early proliferation of terminal effector CD8 T cells by promoting the rapid surface expression of IL2Ralpha during acute viral infection.