JunB plays a crucial role in development of regulatory T cells by promoting IL-2 signaling

Abstract

The AP-1 transcription factor JunB plays crucial roles in multiple biological processes, including placental formation and bone homeostasis. We recently reported that JunB is essential for development of Th17 cells, and thus Junb-deficient mice are resistant to experimental autoimmune encephalomyelitis. However, the role of JunB in CD4 + T cells under other inflammatory disease conditions is unknown. Here we show that mice lacking JunB in CD4 + T cells (Junb fl/fl Cd4-Cre mice) were more susceptible to dextran sulfate sodium (DSS)-induced colitis because of impaired development of regulatory T (Treg) cells. Production of interleukin (IL)-2 and expression of CD25, a high affinity IL-2 receptor component, were decreased in Junb-deficient CD4 + T cells in vitro and in vivo. Naive CD4 + T cells from Junb fl/fl Cd4-Cre mice failed to differentiate into Treg cells in the absence of exogenously added IL-2 in vitro. A mixed bone marrow transfer experiment revealed that defective Treg development of Junb-deficient CD4 + T cells was not rescued by co-transferred wild-type cells, indicating a significance of the cell-intrinsic defect. Injection of IL-2-anti-IL-2 antibody complexes induced expansion of Treg cells and alleviated DSS-induced colitis in Junb fl/fl Cd4-Cre mice. Thus JunB plays a crucial role in the development of Treg cells by facilitating IL-2 signaling.

Transcriptional Regulation of Differentiation and Functions of Effector T Regulatory Cells

“…Mechanistically, JunB promotes DNA-binding of IRF4 at loci of eTreg-related genes containing AICE motifs, on which JunB colocalizes with BATF and IRF4, such as Icos and Ctla4 . Recently, using different JunB-deficient mouse models, other groups also demonstrated that JunB is essential for the expression of eTreg-related molecules [56,57], although the autoimmune phenotypes of their mice are different from those of our mice [56].…”

JunB controls intestinal effector programs in regulatory T cells

“…Previously, we and others found that the AP-1 TF JunB was essential for the differentiation of inflammatory T-helper 17 (Th17) cells 14, 15, 16 , demonstrating that JunB plays subset-restricted roles in T cell programming. More recently, JunB was reported to control differentiation and suppressive functions of eTregs 17 ; however, many of the conclusions from this study are confounded by the use of a CD4-cre-mediated Junb conditional deletion strategy that has since been demonstrated to cause cell-extrinsic defects in Treg development 18 . Because of the predicted role of JunB in tissue-specific Tregs and previous data demonstrating broad and important roles for JunB in Th17 cells, we therefore chose to directly investigate whether JunB was important for tissue-specific functionality in Tregs.…”

“…Importantly, these mechanistic insights were surmised from experiments using Junb f/f CD4 cre mice and mixed bone marrow chimeras derived therefrom 17 , which have since been demonstrated to be problematic models for the assessment of the role of JunB in Treg function. Specifically, Junb f/f CD4 cre mice have impaired thymic Treg differentiation and loss of peripheral Tregs resulting from a Treg-extrinsic defect in IL-2 production by Foxp3 - T cells in the thymus 14, 18 . Moreover, both thymocytes and peripheral T cells from Junb f/f CD4 cre mice are strongly disadvantaged under competitive conditions 18 – irrespective of Foxp3 expression – highlighting an important role for JunB during T cell development or maturation that confounds the observation of JunB-deficient eTreg generation in mixed bone marrow chimeras.…”

“…Specifically, Junb f/f CD4 cre mice have impaired thymic Treg differentiation and loss of peripheral Tregs resulting from a Treg-extrinsic defect in IL-2 production by Foxp3 - T cells in the thymus 14, 18 . Moreover, both thymocytes and peripheral T cells from Junb f/f CD4 cre mice are strongly disadvantaged under competitive conditions 18 – irrespective of Foxp3 expression – highlighting an important role for JunB during T cell development or maturation that confounds the observation of JunB-deficient eTreg generation in mixed bone marrow chimeras. In contrast, our study employs multiple Treg-restricted genetic models to demonstrate that apparent JunB-dependent ICOS expression is due to loss of CD25 - Tregs – rather than direct regulation by JunB – and instead suggests that the importance of JunB in Tregs derives from an essential role in maintenance of both Tfr cells and a novel colonic suppression program.…”

Protective Effect of the α7 Nicotinic Receptor Agonist PNU-282987 on Dopaminergic Neurons Against 6-Hydroxydopamine, Regulating Anti-neuroinflammatory and the Immune Balance Pathways in Rat

“…These transcription factors play a central role in the immune system, including T cell activation, Th differentiation and exhaustion. Katagiri et al (2019) recently found that JunBfl/fl Cd4-Cre mice exhibited a significant reduction in the number of Treg cells and that JunB-/-CD4+ T cells failed to differentiate into Treg cells in vitro, indicating that JunB plays a crucial role in the development of Tregs in a DSS-induced colitis model. Bao et al (2016) also found that AP-1 regulated the activity of the Foxp3 promoter in Treg cells and that adenosine promoted Foxp3 expression in Treg cells during sepsis.…”