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Browsing by Subject "T follicular helper cells"
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Item AMP kinase promotes Bcl6 expression in both mouse and human T cells(Elsevier, 2017-01) Xie, Markus M.; Amet, Tohti; Liu, Hong; Yu, Qigui; Dent, Alexander L.; Department of Microbiology and Immunology, School of MedicineThe transcription factor Bcl6 is a master regulator of follicular helper T (TFH) cells, and understanding the signaling pathway that induces Bcl6 and TFH cell differentiation is therefore critical. IL-2 produced during T cell activation inhibits Bcl6 expression but how TFH cells evade IL-2 inhibition is not completely understood. Here we show that Bcl6 is highly up-regulated in activated CD4 T cells following glucose deprivation (GD), and this pathway is insensitive to inhibition by IL-2. Similar to GD, the glucose analog 2-deoxyglucose (2DG) inhibits glycolysis, and 2DG induced Bcl6 expression in activated CD4 T cells. The metabolic sensor AMP kinase (AMPK) is activated when glycolysis is decreased, and the induction of Bcl6 by GD was inhibited by the AMPK antagonist compound C. Additionally, activation of AMPK by the drug AICAR caused Bcl6 up-regulation in activated CD4 T cells. When mice were immunized with KLH using AICAR as an adjuvant, there was a strong TFH–dependent enhancement of KLH-specific antibody (Ab) responses, and higher Bcl6 expression in TFH cells in vivo. Activation of AMPK strongly induced BCL6 and the up-regulation of TFH cell marker expression by human CD4 T cells. Our data reveal a major new pathway for TFH cell differentiation, conserved by both mouse and human T cells. Mature TFH cells are reported to have a lower metabolic state compared to TH1 cells. Our data indicates that decreased metabolism may be deterministic for TFH cell differentiation, and not simply a result of TFH cell differentiation.Item Development of allergen-specific IgE in a food-allergy model requires precisely timed B cell stimulation and is inhibited by Fgl2(Cell Press, 2022) Chen, Qiang; Xie, Markus; Liu, Hong; Dent, Alexander L.; Microbiology and Immunology, School of MedicineImmunoglobulin E (IgE) responses are a central feature of allergic disease. Using a well-established food-allergy model in mice, we show that two sensitizations with cognate B cell antigen (Ag) and adjuvant 7 days apart promotes optimal development of IgE+ germinal center (GC) B cells and high-affinity IgE production. Intervals of 3 or 14 days between Ag sensitizations lead to loss of IgE+ GC B cells and an undetectable IgE response. The immunosuppressive factors Fgl2 and CD39 are down-regulated in T follicular helper (TFH) cells under optimal IgE-sensitization conditions. Deletion of Fgl2 in TFH and T follicular regulatory (TFR) cells, but not from TFR cells alone, increase Ag-specific IgE levels and IgE-mediated anaphylactic responses. Overall, we find that Ag-specific IgE responses require precisely timed stimulation of IgE+ GC B cells by Ag. Furthermore, we show that Fgl2 is expressed by TFH cells and represses IgE. This work has implications for the development and treatment of food allergies.Item Inhibiting Glycolysis Enhances T Follicular Helper Cell Differentiation and Survival upon Human Immunodeficiency Virus Infection(2020-01) Rane, Sushmita Shirish; Yu, Quigui (Andy); Guo, Haitao; Lu, TaoHuman immunodeficiency virus (HIV) primarily infects T helper (Th) cells. Decrease in the number of Th cells is the hallmark of HIV infection. Latent reservoirs of human immunodeficiency virus (HIV) are the leading barrier towards eradication of HIV infection. T Follicular helper (Tfh) cells are a subset of Th cells that function to provide aid to B cells for their maturation, affinity selection and antibody class switch. Several studies have shown that Tfh cells are a major reservoir of latent as well as productive hiv infection. But in contrast to the fate of other Th cell subsets, the frequency of Tfh cells was shown to have increased during HIV infection which could not be attributed to their reduced susceptibility to HIV infection. The hypothesis was that Tfh cells possess a unique metabolic phenotype that protects them from HIV induced cell death. Transcriptome analysis of Th subsets from human donors and showed that Tfh cells rely less on glycolysis for their energetic requirements and instead have increased transcription of fatty acid synthesis genes. This finding was corroborated by seahorse extracellular flux assay. The results shoId that glycolysis was not essential for Tfh cell differentiation in-vitro. The observed increase in Tfh cell frequency could not be attributed to increased Tfh differentiation upon HIV infection since HIV infection inhibited the differentiation of both non-Tfh and Tfh cells. The results found that bypassing the glycolytic pathway by providing Tfh cells with Galactose in the medium protected ex-vivo infected primary tonsillar cells from HIV induced cell death. This protection could be partly explained by the induction of Baculovirus IAP repeat containing 5 (BIRC5) when the cells utilized Galactose instead of Glucose. The studies together show that Tfh cells have an oxidative metabolic phenotype which protects them from HIV induced cell death in part by induction of BIRC5 expression.Item Roles of T follicular helper cells and T follicular regulatory cells in Autoantibody Production in IL-2-deficient mice(American Association of Immunologists, 2019-07-12) Xie, Markus M.; Liu, Hong; Corn, Caleb; Koh, Byung-Hee; Kaplan, Mark H.; Turner, Matthew J.; Dent, Alexander L.; Microbiology and Immunology, School of MedicineAutoantibodies can result from excessive T follicular helper (Tfh) cell activity, whereas T follicular regulatory (Tfr) cells negatively regulate autoantibody production. IL-2 knockout (KO) mice on the BALB/c background have elevated Tfh responses, produce autoantibodies, and develop lethal autoimmunity. We analyzed Tfh and Tfr cells in IL-2 KO mice on the C57BL/6 (B6) genetic background. In B6 IL-2 KO mice, the spontaneous formation of Tfh cells and germinal center B cells was greatly enhanced, along with production of anti-DNA autoantibodies. IL-2 has been reported to repress Tfr cell differentiation; however, Tfr cells were not increased over wild-type levels in the B6 IL-2 KO mice. To assess Tfh and Tfr cell regulation of autoantibody production in IL-2 KO mice, we generated IL-2 KO mice with a T cell-specific deletion of the master Tfh cell transcription factor Bcl6. In IL-2 KO Bcl6 conditional KO (2KO-Bcl6TC) mice, Tfh cells, Tfr cells, and germinal center B cells were ablated. In contrast to expectations, autoantibody IgG titers in 2KO-Bcl6TC mice were significantly elevated over autoantibody IgG titers in IL-2 KO mice. Specific deletion of Tfr cells with Foxp3-cre Bcl6-flox alleles in IL-2 KO mice led to early lethality, before high levels of autoantibodies could develop. We found IL-2+/+ Tfr cell-deficient mice produce significant levels of autoantibodies. Our overall findings provide evidence that Tfh cells are dispensable for high-level production of autoantibodies and also reveal a complex interplay between Tfh and Tfr cells in autoantibody production and autoimmune disease.