GATA3, HDAC6, and BCL6 Regulate FOXP3+ Treg Plasticity and Determine Treg Conversion into Either Novel Antigen-Presenting Cell-Like Treg or Th1-Treg

Abstract

We conducted an experimental database analysis to determine the expression of 61 CD4+ Th subset regulators in human and murine tissues, cells, and in T-regulatory cells (Treg) in physiological and pathological conditions. We made the following significant findings: (1) adipose tissues of diabetic patients with insulin resistance upregulated various Th effector subset regulators; (2) in skin biopsy from patients with psoriasis, and in blood cells from patients with lupus, effector Th subset regulators were more upregulated than downregulated; (3) in rosiglitazone induced failing hearts in ApoE-deficient (KO) mice, various Th subset regulators were upregulated rather than downregulated; (4) aortic endothelial cells activated by proatherogenic stimuli secrete several Th subset-promoting cytokines; (5) in Treg from follicular Th (Tfh)-transcription factor (TF) Bcl6 KO mice, various Th subset regulators were upregulated; whereas in Treg from Th2-TF GATA3 KO mice and HDAC6 KO mice, various Th subset regulators were downregulated, suggesting that Bcl6 inhibits, GATA3 and HDAC6 promote, Treg plasticity; and (6) GATA3 KO, and Bcl6 KO Treg upregulated MHC II molecules and T cell co-stimulation receptors, suggesting that GATA3 and BCL6 inhibit Treg from becoming novel APC-Treg. Our data implies that while HDAC6 and Bcl6 are important regulators of Treg plasticity, GATA3 determine the fate of plastic Tregby controlling whether it will convert in to either Th1-Treg or APC-T-reg. Our results have provided novel insights on Treg plasticity into APC-Treg and Th1-Treg, and new therapeutic targets in metabolic diseases, autoimmune diseases, and inflammatory disorders.

DNA Checkpoint and Repair Factors Are Nuclear Sensors for Intracellular Organelle Stresses—Inflammations and Cancers Can Have High Genomic Risks

“…The genes that are not expressed is shown as () (Supplementary Table 2 ). The method of calculation the threshold is shown in Supplemental Figure 1 and was explained previously (Wang X. et al, 2016 ; Wang et al, 2017 ; Xu et al, 2018 ).…”

“…An experimental data mining strategy (Figure 1 ) was used to analyze the expression profiles of mRNA transcripts of 26 DDCF and 42 DDRF genes in 21 different human and 20 mouse tissues including heart and vasculature as we previously described (Xu et al, 2018 ).…”

Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis

“…Thus, anti-inflammatory treatment has been presumed a promising therapy to control the local inflammation and promote desired neovascularization. TGF- β , IL-10, and newly discovered cytokine IL-35 are three primary anti-inflammatory cytokines secreted by Tregs, which are the critical immunosuppressive cells in our body ( 13 , 26 , 82 , 83 ). TGF- β is a multifunctional regulator constitutively expressed in many tissues ( 4 ), while IL-10 and IL-35 are inflammation-induced anti-inflammatory cytokines ( 4 ).…”

Lysophospholipids induce innate immune transdifferentiation of endothelial cells, resulting in prolonged endothelial activation

“…Nevertheless, LPC and LPI could both induce EC activation marker genes, such as adhesion molecules, cytokines, and chemokines. More importantly, they could both induce innate immune reprogramming/transdifferentiation of ECs into innate immune cells by up-regulating additional DAMP receptors, such as CD36, to receive additional DAMPs for prolonged/ sustained activation and MHC-II molecules, such as HLA-DRB1, to present endothelial cell-specific and non-ECspecific self-antigen epitopes to activate T cells (12,44). Similar to the findings in the present study on cell transdifferentiation, we also reported recently that in response to environmental stimulations, including DAMPs, hypoxia, and master gene mutations, cell identification could be plastic.…”

“…Similar to the findings in the present study on cell transdifferentiation, we also reported recently that in response to environmental stimulations, including DAMPs, hypoxia, and master gene mutations, cell identification could be plastic. First, transcription factor GATA-binding protein 3 (GATA3), histone deacetylase 6 (HDAC6), and B-cell lymphoma 6 (BCL6) regulate forkhead box P3 (FOXP3) ϩ regulatory T cell (Treg) plasticity and determine Treg conversion into either novel antigen-presenting cell-like or type 1 T-helper cell Tregs (12), which further corroborates our recently proposed new working model that pathological conditions reshape physiological Tregs into pathological Tregs (45). Second, thrombus leukocytes exhibit more endothelial cell-specific angiogenic markers than do peripheral blood leukocytes in acute coronary syndrome patients, suggesting a possibility of transdifferentiation of leukocytes into angiogenic endothelial cells (46).…”