Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 232-263). Also available online.

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xiii, 136 p.; also includes graphics (some col.) Includes bibliographical references (p. 120-136). Available online via OhioLINK's ETD Center

Sepsis-induced myeloid-derived suppressor cells (MDSCs) contribute to immunosuppression associated with sepsis. We reported that the CCAAT enhancer-binding protein C/EBPβ activates microRNA (miR)-21 and miR-181b expressions, which induce transcription factor NFI-A to support the generation and expansion of MDSCs in the bone marrow and spleens of septic mice. Here, using a conditional knockout mouse model lacking C/EBPβ in the myeloid lineage, we find that without C/EBPβ, myeloid progenitor cells could not express miR-21 or miR-181b, and ectopic expression of C/EBPβ in the C/EBPβ-deficient myeloid progenitors activated the expression of the two miRNAs. Moreover, C/EBPβ-reconstituted myeloid cells expressed IL-10 and reduced T cell proliferation and function, similar to control MDSCs that express C/EBPβ. Exogenous expression of miR-21 and miR-181b in the C/EBPβ-deficient myeloid progenitors from septic mice produced similar results. Notably, NFI-A-dependent transactivation of NF-kB MDSC generating pathway was reversed in the C/EBPβ-deficient myeloid progenitors from septic mice. Together, these results support that decreasing C/EBPβ expression prevents MDSC generation and decreases immunosuppression in septic mice, providing a target for sepsis treatment.

Superantigens are exotoxins produced by Staphylococcus aureus and induce extensive T cell proliferation and proinflammatory cytokines, leading to toxic shock syndrome at high concentrations. However, the role of superantigens produced at relatively low concentrations during asymptomatic colonization or chronic infection has not been well established. In this dissertation, we demonstrated that stimulation of human PBMCs with staphylococcal enterotoxin C1 (SEC1) at the dose inducing a half maximal T cell proliferation (suboptimal stimulation) induced immunosuppressive CD4+CD25+FOXP3+ and CD8+CD25+FOXP3+ T cells. The suppression of these cells was mainly mediated by the galectin-1. We found that suboptimal stimulation with SEC1 induced differential activation of PI3K-mTOR-Akt pathway, leading to expression of FOXP3 isoforms preferably localized to the nucleus and induction of PTEN that contributes to maintain stability and suppressive activity of regulatory T cells. Taken together, these results demonstrate the important role of superantigen produced at low concentration during asymptomatic colonization that induce immunosuppressive CD4+ and CD8+ regulatory T cells to promote survival, propagation, and colonization for S. aureus in the host.

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Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第25167号 / 医博第5053号 / 新制||医||1071(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 椛島 健治, 教授 濵﨑 洋子 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM