UBC Theses and Dissertations
Innate regulation of TSST-1 induced immune response by peripheral blood γδ T cells Kalyan, Shirin
Toxic shock syndrome toxin-1 (TSST-1) is the staphylococcal superantigen (sAg) identified as being the primary causative agent of menstrual toxic shock syndrome (TSS), and it is among the main sAg’s responsible for non-menstrual TSS. Superantigens are the most potent T cell mitogens known. They induce the massive secretion of inflammatory cytokines by bypassing the processing and presentation requirement of conventional peptide antigens and by binding as intact proteins directly to the MHC class II on antigen presenting cells and to specific Vβ-chains of the αβ T cell receptor. This interaction results in an inflammatory cascade that has the potential to lead to hypotension, shock, and death. TSST-1 is expressed by at least 20% of S. aureus clinical isolates; however, not everyone exposed to this sAg succumbs to TSS. Apart from protective antibodies, the factors in the immediate microenvironment which dictate the course of the immune response leading to a deleterious inflammatory reaction are largely unknown. γδ T cells are a unique subset of innate T lymphocytes that are credited with linking the innate and adaptive immune system as they serve as the first line of defense [i.e. defence] against both infectious and non-infectious stress. The objective of this study was to determine if and how human peripheral blood γδ T cells may influence the course of TSST-1 induced inflammation. High mobility group box-1 protein (HMGB-1) was investigated as an indicator of the downstream consequence of γδ T cell activity in TSST-1 pathogenesis. HMGB-1 is a nuclear protein that was previously found to be secreted by LPS-stimulated macrophages, and was determined to be the late mediator of endotoxin shock since neutralizing its effects as late as 24 hours following sepsis was sufficient to rescue mice from lethality. This study established that γδ T cells potently exacerbate the early inflammatory response to TSST-1 and enhance the subsequent secretion of HMGB-1. γδ T cells mediate this effect by inducing early monocyte maturation and upregulating the expression of CD40 which plays a pivotal role in TSST-1 pathogenesis. The results of this study lend support to the notion that γδ T cells play an important role in linking the innate and adaptive immune responses to TSST-1.
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