CIP2A Constrains Th17 Differentiation by Modulating STAT3 Signaling

Abstract

Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) is an oncogene and a potential cancer therapy target protein. Accordingly, a better understanding of the physiological function of CIP2A, especially in the context of immune cells, is a prerequisite for its exploitation in cancer therapy.Here, we report that CIP2A negatively regulates interleukin (IL)-17 production by Th17 cells in human and mouse. Interestingly, concomitant with increased IL-17 production, CIP2A-deficient Th17 cells had increased strength and duration of STAT3 phosphorylation. We analyzed the interactome of phosphorylated STAT3 in CIP2A-deficient and CIP2A-sufficient Th17 cells and indicated together with genome-wide gene expression profiling, a role of Acylglycerol Kinase (AGK) in the regulation of Th17 differentiation by CIP2A. We demonstrated that CIP2A regulates the strength of the interaction between AGK and STAT3, and thereby modulates STAT3 phosphorylation and expression of IL-17 in Th17 cells.

LncRNA-BG Inhibited Th17 Cells Differentiation By Targeting RORγt Protein.

“…As an important subset of CD4 + T lymphocytes, Th17 cells protected the mucosal surface mainly by secreting IL-17 and play a pivotal role in host defense against pathogens such as fungi and extracellular bacteria [23,24]. However, Th17 differentiation disorder produced excessive IL-17A could induce autoimmune tissue damages and in ammatory diseases [25,26]. IL-23 is a key cytokine for Th17 cell development and activation.…”

Quantitative genome-scale metabolic modeling of human CD4+ T cell differentiation reveals subset-specific regulation of glycosphingolipid pathways

“…Human CD4 + T cell isolation, activation, and differentiation CD4 + T cells were isolated from umbilical cord blood as described previously by (Hawkins et al, 2013;Khan et al, 2020;Tripathi et al, 2017;Ubaid Ullah et al, 2018). Human umbilical cord blood was layered on ficol (GE Healthcare, cat# 17-1440-03) for isolation of white blood cells.…”

“…Human CD4 + T cells isolated from the human umbilical cord blood as described previously (Hawkins et al, 2013;Khan et al, 2020;Tripathi et al, 2017;Ubaid Ullah et al, 2018). The use of the blood of unknown donors was approved by the Ethics Committee of the Hospital District of Southwest Finland (24.11.1998, article 323).…”

Quantitative analysis and genome-scale modeling of human CD4+T-cell differentiation reveals subset-specific regulation of glycosphingolipid pathways

“…CD4 + T-cells were isolated from human umbilical cord blood as described previously [56, 62, 63]. For Th17 cell differentiation, isolated CD4 + cells were activated with a combination of plate-bound anti-CD3 (750 ng/24-well culture plate well; Immunotech/Beckman Coulter REF # IM-1304) and soluble anti-CD28 ((1ug/mL; Immunotech/Beckman coulter REF # IM1376) antibodies in serum-free X-Vivo 20 medium (Lonza), in the absence (Th0) or presence (Th17) of IL-6 (20ng/ml, Roche, Cat# 11138600 001); IL-1β (10ng/ml, R&D Systems Cat # 201 LB); TGF-β1 (10ng/ml, R&D Systems Cat# 240); anti-IL-4 (1 μg/ml) R&D Systems Cat# MAB204) and anti-IFN-γ (1 μg/ml R&D Systems Cat#MAB-285).…”