Nuclear Factor of Activated T Cells Regulates the Expression of Interleukin-4 in Th2 Cells in an All-or-none Fashion

It is well established that the cytokine IL-12 and the transcription factor STAT4, an essential part of the IL-12 signaling pathway, are critical components of the Th1 differentiation process in T cells. In response to pathogenic stimuli, this process causes T cells to proliferate rapidly and secrete high amounts of the cytokine IFN-γ, leading to the Th1 proinflammatory phenotype. However, there are still unknown components of this differentiation pathway. We here demonstrated that the expression of the histone methyltransferase Mll1 is driven by IL-12 signaling through STAT4 in humans and mice and is critical for the proper differentiation of a naïve T cell to a Th1 cell. Once MLL1 is up-regulated by IL-12, it regulates the proliferation of Th1 cells. As evidence of this, we show that Th1 cells from Mll1(+/-) mice are unable to proliferate rapidly in a Th1 environment in vitro and in vivo. Additionally, upon restimulation with cognate antigen Mll1(+/-), T cells do not convert to a Th1 phenotype, as characterized by IFN-γ output. Furthermore, we observed a reduction in IFN-γ production and proliferation in human peripheral blood stimulated with tetanus toxoid by use of a specific inhibitor of the MLL1/menin complex. Together, our results demonstrate that the MLL1 gene plays a previously unrecognized but essential role in Th1 cell biology and furthermore, describes a novel pathway through which Mll1 expression is regulated.

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“…2D and E). We did not observe significant binding to confirmed STAT6-binding sites in humans [44] or mice [45] (Supplemental Fig. 2D and E).…”

Section: Il-12 Causes Stat4-dependent Mll1 Expressionmentioning

confidence: 77%

Epigenetic regulation of IL-12-dependent T cell proliferation

Schaller

Ito

Allen

et al. 2015

Journal of Leukocyte Biology

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“…Although heterogeneity of Th2 cells can be a result of differential epigenetic status of each cytokine allele 215, 216 , the actual cytokine production in a given cell upon a single round of stimulation may be a stochastic event 217 . Heterogeneous activation of transcription factors such as NFAT or differential assembly of functional transcription factor complex needed for inducing cytokine production may be one of the main explanations 217, 218 . Thus, IL-4- and/or IL-13-non-producing cells identified after stimulation at one time may express these cytokines in response to another round of stimulation.…”

Section: Induction Of Il-4 and Il-13 Expression By Th2 Cellsmentioning

confidence: 99%

T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production

2015

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Interleukin-4 (IL-4), IL-5 and IL-13, the signature cytokines that are produced during type 2 immune responses, are critical for protective immunity against infections of extracellular parasites and are responsible for asthma and many other allergic inflammatory diseases. Although many immune cell types within the myeloid lineage compartment including basophils, eosinophils and mast cells are capable of producing at least one of these cytokines, the production of these “type 2 immune response-related” cytokines by lymphoid lineages, CD4 T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) in particular, are the central events during type 2 immune responses. In this review, I will focus on the signaling pathways and key molecules that determine the differentiation of naïve CD4 T cells into Th2 cells, and how the expression of Th2 cytokines, especially IL-4 and IL-13, is regulated in Th2 cells. The similarities and differences in the differentiation of Th2 cells, IL-4-producing T follicular helper (Tfh) cells and ILC2s as well as their relationships will also be discussed.

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“…However, a recent investigation showed that a single peptide/MHC complex can initiate the response of CD4 + T cell and that additional pMHC molecules do not increase the secretion of effector cytokines (such as IL-2 or TNFa), demonstrating an ‘all or none’ type of response [137]. The follow-up of the secretion of Th2 cytokine, IL-4, strictly requires the presence of NFAT in the nucleus and analogue differences in TCR triggering are converted into digital outcome of NFAT nuclear translocation [138]. It is noteworthy that activation of NFAT itself is a digital process because it requires the complete—highly cooperative—dephosphorylation by CaN of 13 serine residues, which hide the nuclear localization signal segment inside the protein [139].…”

Section: Analogue and Digital Signalling In T Lymphocytesmentioning

confidence: 99%

“…At the same time, MAPK responds gradually to stimulation of Jurkat cells with SDF-1, reflecting plasticity in the reaction of T cells to chemokine gradients [141]. In addition, the activation of NFκB showed analogue [138] and digital [142] modes after gradual T cell stimulation.…”

Section: Analogue and Digital Signalling In T Lymphocytesmentioning

confidence: 99%

“…Short-term translocation of NFAT in the nucleus induces a tolerance programme, whereas prolonged retention upregulates the activation programme [98]. Sustained residence of NFAT in the nucleus is strictly necessary for IL-4 synthesis [138]. As described above, EGFR and NGFR can rewire the MAPK module depending on activation of PKC involving a positive feedback loop [143].…”

Section: Analogue and Digital Signalling In T Lymphocytesmentioning

confidence: 99%

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Computational properties of mitochondria in T cell activation and fate

2016

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In this article, we review how mitochondrial Ca2+ transport (mitochondrial Ca2+ uptake and Na+/Ca2+ exchange) is involved in T cell biology, including activation and differentiation through shaping cellular Ca2+ signals. Based on recent observations, we propose that the Ca2+ crosstalk between mitochondria, endoplasmic reticulum and cytoplasm may form a proportional–integral–derivative (PID) controller. This PID mechanism (which is well known in engineering) could be responsible for computing cellular decisions. In addition, we point out the importance of analogue and digital signal processing in T cell life and implication of mitochondrial Ca2+ transport in this process.

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Nuclear Factor of Activated T Cells Regulates the Expression of Interleukin-4 in Th2 Cells in an All-or-none Fashion

Cited by 23 publications

References 35 publications

Epigenetic regulation of IL-12-dependent T cell proliferation

Epigenetic regulation of IL-12-dependent T cell proliferation

T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production

Computational properties of mitochondria in T cell activation and fate

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