Contributions
Abstract: P477
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
Background: The development and progression of multiple sclerosis (MS) and other autoimmune disorders, results in part from a dysbalance between pathogenicity of effector CD4+ T cells and negative regulation imposed by regulatory T cells. Oxysterols, cholesterol metabolites, have recently been assigned novel functions in modulating the immune response during MS and its animal model, the experimental autoimmune encephalomyelitis (EAE). However, neither their roles nor their mechanisms of actions have been assessed in CD4+ T lymphocytes.
Objectives: We here proposed to assess oxysterol expression levels in subsets of CD4+ T helper and further examined their function and mechanisms of action during autoimmunity.
Methods: Subsets of CD4+ Thelper cells were generated in vitro and in vivo and expression levels of oxysterol converting enzymes were examined by real-time PCR. Secretion of oxysterols was measured by mass-spectrometry in T cells obtained in vitro. Oxysterol functions and downstream signaling were assessed using oxysterols-deficient T cells.
Results: We showed that the oxysterol 25-hydroxycholesterol (25-OHC) and transcript levels of its synthesizing enzyme, cholesterol 25 hydroxylase (Ch25h), were specifically increased in IL-27-induced Type 1 regulatory T (TR1) cells. IL-27, a critical factor for TR1 cell differentiation is instrumental in preventing autoimmune diseases and MS. We demonstrated that 25-OHC acts as negative regulators of TR1 cells in particular on IL-10 secretion via LXR signalling. Furthermore, 25-OHC lead to intracellular cholesterol accumulation within TR1 cells, another mechanism described in innate immune cells to enhance inflammatory processes.
Conclusion: Together, our findings show that Ch25h and 25-OHC act as negative regulators of TR1 cells both in vitro and in vivo. The production of 25-OHC by TR1 cells is in agreement with the existence of an autocrine and paracrine 25-OHC/ LXR amplification loop, inhibiting both TR1 cell polarization and cholesterol efflux as well as enhancing cholesterol production. Understanding the complex interaction between the metabolic and immune systems may lead to substantial therapeutic promises for harnessing autoimmune disorders.
Disclosure: Nothing to disclose
Abstract: P477
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
Background: The development and progression of multiple sclerosis (MS) and other autoimmune disorders, results in part from a dysbalance between pathogenicity of effector CD4+ T cells and negative regulation imposed by regulatory T cells. Oxysterols, cholesterol metabolites, have recently been assigned novel functions in modulating the immune response during MS and its animal model, the experimental autoimmune encephalomyelitis (EAE). However, neither their roles nor their mechanisms of actions have been assessed in CD4+ T lymphocytes.
Objectives: We here proposed to assess oxysterol expression levels in subsets of CD4+ T helper and further examined their function and mechanisms of action during autoimmunity.
Methods: Subsets of CD4+ Thelper cells were generated in vitro and in vivo and expression levels of oxysterol converting enzymes were examined by real-time PCR. Secretion of oxysterols was measured by mass-spectrometry in T cells obtained in vitro. Oxysterol functions and downstream signaling were assessed using oxysterols-deficient T cells.
Results: We showed that the oxysterol 25-hydroxycholesterol (25-OHC) and transcript levels of its synthesizing enzyme, cholesterol 25 hydroxylase (Ch25h), were specifically increased in IL-27-induced Type 1 regulatory T (TR1) cells. IL-27, a critical factor for TR1 cell differentiation is instrumental in preventing autoimmune diseases and MS. We demonstrated that 25-OHC acts as negative regulators of TR1 cells in particular on IL-10 secretion via LXR signalling. Furthermore, 25-OHC lead to intracellular cholesterol accumulation within TR1 cells, another mechanism described in innate immune cells to enhance inflammatory processes.
Conclusion: Together, our findings show that Ch25h and 25-OHC act as negative regulators of TR1 cells both in vitro and in vivo. The production of 25-OHC by TR1 cells is in agreement with the existence of an autocrine and paracrine 25-OHC/ LXR amplification loop, inhibiting both TR1 cell polarization and cholesterol efflux as well as enhancing cholesterol production. Understanding the complex interaction between the metabolic and immune systems may lead to substantial therapeutic promises for harnessing autoimmune disorders.
Disclosure: Nothing to disclose