Immune tolerance induced by resistin-treated dendritic cells or lipoteichoic acid-treated effector T cells

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서울대학교 대학원
Regulatory T cells (Tregs) suppress the immune responses of self- or non-self-reactive T cells in peripheral tissues and organs. It has been known that tolerogenic dendritic cells (tDCs) are acting as a main inducer to increase the expansion and differentiation of Tregs. Resistin, one of the adipokines, appears to have a capacity to resist insulin signaling in mouse. However, resistin in human and pigs is mainly produced from mononuclear immune cells and epithelial cells, and therefore it has been studied for its immunomodulatory functions. Lipoteichoic acid (LTA) is a unique cell surface component of gram positive bacteria such as Staphylococcus aureus and induces TLR2 signal transduction.
Recent studies have been focused on the expansion of Tregs which are induced by tDCs to regulate immune responses such as allergic diseases, autoimmune diseases and organ transplantation. Despite that resistin is reasonably well known to be involved in the immune diseases though the control of function of macrophages, there are no reports on the relationship between resistin and DCs. Therefore, I examined whether resistin regulates the function of DCs and expansion of Tregs. On the other hand, TLR signaling could regulate the proliferation of T cells activated through TCR stimulation in a TLR ligand-dependent manner. Therefore, I further examined how LTA affects the proliferation of antigen-specific CD4+ T cells.
To investigate the roles of resistin and LTA in DCs and T cells, following studies have been performed ; 1) the effects of resistin to control the antigen-uptake, cytokine production and T cell stimulation of DCs, 2) resistin-mediated DCs to induce the expansion of Tregs, and 3) the effects of LTA in antigen-specific CD4+ T cells. The results showed that resistin inhibited antigen uptake and the production of LTA-induced cytokines in DCs. Furthermore, DCs treated with resistin suppressed proliferation and differentiation of T cells. Resistin increased the expression of Foxp3 mRNA in peripheral blood mononuclear cells (PBMCs) while no response in CD4+ T cells only. It was noting that resistin-treated DCs increased the production of Foxp3 in CD4+ CD25+ T cells but not in CD4+CD25- naïve T cells. When TGF-β receptor was blocked, no CD4+CD25+Foxp3+ Tregs were increased. The results demonstrated that resistin-treated DCs showing tolerogenic characteristics increased the expansion of Tregs and suppressed effector cells.
Finally, to investigate the effects of LTA on the effector CD4+ T cells, naïve CD4+ T cells were co-cultured with S. aureuse-pulsed DCs. Effector CD4+ T cells produced high levels of IFN-γ, CD25, CD69, and TLRs 2 and 4. When LTA was treated to the effector CD4+ T cells, the production of membrane bound form TGF-β and Foxp3 were increased. The proliferation of effector CD4+ T cells was decreased by LTA treatment. When TGF-β signaling was blocked by treatment of TGF-β receptor inhibitor, LTA failed to suppress the proliferation of S. aureus-specific CD4+ T cells. The results showed that LTA suppress the proliferation of S. aureus-specific CD4+ T cells via enhancement of TGF-β production.
In conclusion 1) resistin suppresses the antigen uptake, cytokine production and T cell stimulation in DCs, 2) resistin-treated DCs induce the expansion of Tregs, and 3) LTA regulates the proliferation of antigen-specific T cells. Therefore, resistin-treated DCs and effector T cells stimulated with LTA enhanced the activity of Tregs.
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College of Agriculture and Life Sciences (농업생명과학대학)Dept. of Agricultural Biotechnology (농생명공학부)Theses (Ph.D. / Sc.D._농생명공학부)
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