Reversal of Abnormal CD4+ T Cell Metabolism Alleviates Thyroiditis by Deactivating the mTOR/HIF1a/Glycolysis Pathway

BackgroundHashimoto’s thyroiditis (HT) is an autoimmune disease that features activation of thyroid antigen-specific helper T cells. HT patients have increased Th1 and Th17 T cell subsets. Glycolysis supports chronic activation of Th1 and Th17 T cells, but how this contributes to HT remains unknown.MethodsThe metabolism of CD4+ T cells from 30 HT patients and 30 healthy controls was evaluated by determining the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR). Mice in a subacute thyroiditis (SAT) model were treated with 2DG, metformin, or combination. Metrics of mTOR/HIF-1α/HK2/glycolysis were measured by western blot and Seahorse assay methods. The severity of SAT was measured by flow cytometry and HE staining.ResultsCD4+ T cells from HT patients had enhanced ECAR and OCR. Levels of Glut1, HK2, PKM2, and LDHA in cultured HT CD4+ T cells were elevated. The expression of HK2 and PKM2 in cultured SAT CD4+ T cells was elevated compared with the control group. Activation of the mTOR and HIF-1α pathways was significant in SAT mice, and expression of HIF-1α in the 2DG treated group was reduced. Treatment with 2DG and/or metformin significantly decreased the ratio of Th17 and Th1 T cells.ConclusionsThyroiditis results in elevation of the mTOR/HIF-1α/HK2/glycolysis pathway in CD4+ T cells. The activation of this pathway is reduced by treatment with 2DG and metformin, which also reverted imbalances in CD4+ T cell differentiation.

Pathogenesis

Hashimoto's thyroiditis (HT) is one of the most prevalent autoimmune diseases provoked in genetically susceptible individuals by several triggers. Immune-regulatory genes such as HLA, CTLA-4, and PTPN22 play a major role in the pathogenesis of autoimmune thyroiditis. The thyroid-specific gene currently showing the association with HT (and also Graves' disease) is the gene for thyroglobulin (Tg). The VDR gene is another HT predisposing gene, common for other organ-specific autoimmune diseases such as type-I diabetes or Addison's disease. Furthermore, cytokine genes such as IFN-γ, IL-4, or TGF-β indicate the association with the development and severity of HT. A complex interaction between genetic and non-genetic factors results in enhanced thyroid antigen presentation and reduced immune tolerance leading to predominantly Th1-type autoimmunity, thyroid destruction, and clinical disease. The exact mechanisms of initiation and progression of HT are yet to be clarified. This chapter explores the pathogenesis of Hashimoto's disease.