Highlights • PTMs including acetylation, ubiquitination, and phosphorylation can decorate FoxP3. • PTMs affect FoxP3 DNA binding, transcriptional activation, and proteasomal degradation. • PTMs may ...enable transient regulation of FoxP3 function in response to environmental cues. • A holistic understanding of how these PTMs regulate FoxP3 function in vivo is necessary.
Stable Foxp3 expression is required for the development of functional regulatory T (Treg) cells. Here, we demonstrate that the expression of the transcription factor Foxp3 can be regulated through ...the polyubiquitination of multiple lysine residues, resulting in proteasome-mediated degradation. Expression of the deubiquitinase (DUB) USP7 was found to be upregulated and active in Treg cells, being associated with Foxp3 in the nucleus. Ectopic expression of USP7 decreased Foxp3 polyubiquitination and increased Foxp3 expression. Conversely, either treatment with DUB inhibitor or USP7 knockdown decreased endogenous Foxp3 protein expression and decreased Treg-cell-mediated suppression in vitro. Furthermore, in a murine adoptive-transfer-induced colitis model, either inhibition of DUB activity or USP7 knockdown in Treg cells abrogated their ability to resolve inflammation in vivo. Our data reveal a molecular mechanism in which rapid temporal control of Foxp3 expression in Treg cells can be regulated by USP7, thereby modulating Treg cell numbers and function.
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•DUBs regulate Foxp3 protein expression through the inhibition of degradation•Expression of the DUB USP7 is selectively upregulated during Treg cell differentiation•Foxp3 protein expression is increased by USP7-mediated Foxp3 deubiquitination•USP7 modulates Treg-cell-mediated suppression both in vitro and in vivo
Relevance of mitogen‐activated protein kinases ERK, JNK, and p38 in the regulation of myeloid differentiation.
The MAPKs are a family of serine/threonine kinases that play an essential role in ...connecting cell‐surface receptors to changes in transcriptional programs. MAPKs are part of a three‐component kinase module consisting of a MAPK, an upstream MEK, and a MEKK that couples the signals from cell‐surface receptors to trigger downstream pathways. Three major groups of MAPKs have been characterized in mammals, including ERKs, JNKs, and p38MAPKs. Over the last decade, extensive work has established that these proteins play critical roles in the regulation of a wide variety of cellular processes including cell growth, migration, proliferation, differentiation, and survival. It has been demonstrated that ERK, JNK, and p38MAPK activity can be regulated in response to a plethora of hematopoietic cytokines and growth factors that play critical roles in hematopoiesis. In this review, we summarize the current understanding of MAPK function in the regulation of hematopoiesis in general and myelopoiesis in particular. In addition, the consequences of aberrant MAPK activation in the pathogenesis of various myeloid malignancies will be discussed.
Epidermal growth factor receptor (EGFR) is known to be critically involved in tissue development and homeostasis as well as in the pathogenesis of cancer. Here we showed that Foxp3+ regulatory T ...(Treg) cells express EGFR under inflammatory conditions. Stimulation with the EGF-like growth factor Amphiregulin (AREG) markedly enhanced Treg cell function in vitro, and in a colitis and tumor vaccination model we showed that AREG was critical for efficient Treg cell function in vivo. In addition, mast cell-derived AREG fully restored optimal Treg cell function. These findings reveal EGFR as a component in the regulation of local immune responses and establish a link between mast cells and Treg cells. Targeting of this immune regulatory mechanism may contribute to the therapeutic successes of EGFR-targeting treatments in cancer patients.
▸ Regulatory T (Treg) cells express EGFR ▸ Amphiregulin (AREG) enhances Treg cell function in in vitro suppression assays ▸ AREG enhances Treg cell function in vivo in a colitis and a tumor vaccination model ▸ Mast cell-derived AREG can fully restore optimal Treg cell function
Dendritic cells (DCs) represent a small and heterogeneous fraction of the hematopoietic system, specialized in antigen capture, processing, and presentation. The different DC subsets act as sentinels ...throughout the body and perform a key role in the induction of immunogenic as well as tolerogenic immune responses. Because of their limited lifespan, continuous replenishment of DC is required. Whereas the importance of GM-CSF in regulating DC homeostasis has long been underestimated, this cytokine is currently considered a critical factor for DC development under both steady-state and inflammatory conditions. Regulation of cellular actions by GM-CSF depends on the activation of intracellular signaling modules, including JAK/STAT, MAPK, PI3K, and canonical NF-κB. By directing the activity of transcription factors and other cellular effector proteins, these pathways influence differentiation, survival and/or proliferation of uncommitted hematopoietic progenitors, and DC subset–specific precursors, thereby contributing to specific aspects of DC subset development. The specific intracellular events resulting from GM-CSF–induced signaling provide a molecular explanation for GM-CSF–dependent subset distribution as well as clues to the specific characteristics and functions of GM-CSF–differentiated DCs compared with DCs generated by fms-related tyrosine kinase 3 ligand. This knowledge can be used to identify therapeutic targets to improve GM-CSF–dependent DC-based strategies to regulate immunity.
Colorectal cancer (CRC) is a heterogeneous disease with one of the highest rates of incidence and mortality among cancers worldwide. Understanding the CRC tumor microenvironment (TME) is essential to ...improve diagnosis and treatment. Within the CRC TME, tumor-infiltrating lymphocytes (TILs) consist of a heterogeneous mixture of adaptive immune cells composed of mainly anti-tumor effector T cells (CD4+ and CD8+ subpopulations), and suppressive regulatory CD4+ T (Treg) cells. The balance between these two populations is critical in anti-tumor immunity. In general, while tumor antigen-specific T cell responses are observed, tumor clearance frequently does not occur. Treg cells are considered to play an important role in tumor immune escape by hampering effective anti-tumor immune responses. Therefore, CRC-tumors with increased numbers of Treg cells have been associated with promoting tumor development, immunotherapy failure, and a poorer prognosis. Enrichment of Treg cells in CRC can have multiple causes including their differentiation, recruitment, and preferential transcriptional and metabolic adaptation to the TME. Targeting tumor-associated Treg cell may be an effective addition to current immunotherapy approaches. Strategies for depleting Treg cells, such as low-dose cyclophosphamide treatment, or targeting one or more checkpoint receptors such as CTLA-4 with PD-1 with monoclonal antibodies, have been explored. These have resulted in activation of anti-tumor immune responses in CRC-patients. Overall, it seems likely that CRC-associated Treg cells play an important role in determining the success of such therapeutic approaches. Here, we review our understanding of the role of Treg cells in CRC, the possible mechanisms that support their homeostasis in the tumor microenvironment, and current approaches for manipulating Treg cells function in cancer.
Developing sympathetic neurons die by apoptosis when deprived of NGF. BIM, a BH3-only member of the BCL-2 family, is induced after NGF withdrawal in these cells and contributes to NGF ...withdrawal-induced death. Here, we have investigated the involvement of the Forkhead box, class O (FOXO) subfamily of Forkhead transcription factors in the regulation of BIM expression by NGF. We find that overexpression of FOXO transcription factors induces BIM expression and promotes death of sympathetic neurons in a BIM-dependent manner. In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. Finally, we show that FOXO activity contributes to the NGF deprivation-induced death of sympathetic neurons.
Foxp3 is crucial for both the development and function of regulatory T (Treg) cells; however, the posttranslational mechanisms regulating Foxp3 transcriptional output remain poorly defined. Here, we ...demonstrate that T cell factor 1 (TCF1) and Foxp3 associates in Treg cells and that active Wnt signaling disrupts Foxp3 transcriptional activity. A global chromatin immunoprecipitation sequencing comparison in Treg cells revealed considerable overlap between Foxp3 and Wnt target genes. The activation of Wnt signaling reduced Treg-mediated suppression both in vitro and in vivo, whereas disruption of Wnt signaling in Treg cells enhanced their suppressive capacity. The activation of effector T cells increased Wnt3a production, and Wnt3a levels were found to be greatly increased in mononuclear cells isolated from synovial fluid versus peripheral blood of arthritis patients. We propose a model in which Wnt produced under inflammatory conditions represses Treg cell function, allowing a productive immune response, but, if uncontrolled, could lead to the development of autoimmunity.
•TCF/β-catenin and Foxp3 share common transcriptional targets•Wnt signaling negatively modulates Foxp3 transcriptional activity•Wnt signaling reduces Treg-cell-mediated suppression in vitro and in vivo•Wnt production is increased upon the activation of T cells and at inflammatory loci
Lymphocytes have evolved to react rapidly and robustly to changes in their local environment by using transient adaptations and by regulating their terminal differentiation programmes. Forkhead box ...transcription factors (FTFs) can direct leukocyte-specific responses, and their functional diversification promotes a high degree of context-dependent specification. Many, often antagonistic, FTFs have overlapping expression patterns and can thereby compete for binding to the same chromosomal target sequences. Multiple molecular mechanisms also connect extracellular signals to the expression and functionality of specific FTFs and, in this way, fine-tune their activity. Through these diverse mechanisms, FTFs can function as context-dependent rheostats responding to diverse environmental stimuli. Focusing on the various mechanisms by which their functional activity is modulated, as well as on their mechanisms of action, we discuss how specific FTFs control lymphocyte function, allowing for the establishment and maintenance of immune homeostasis.
The epithelial to mensenchymal transition program regulates various aspects of embryonic development and tissue homeostasis, but aberrant activation of this pathway in cancer contributes to tumor ...progression and metastasis. TGF-b potently induces an epithelial to mensenchymal transition in cancers of epithelial origin by inducing transcriptional changes mediated by several key transcription factors. Here, we identify the developmental transcription factor SOX4 as a transcriptional target of TGF-b in immortalized human mammary epithelial cells. SOX4 expression and activity are rapidly induced in the early stages of the TGF-b-induced epithelial to mensenchymal transition. We demonstrate that conditional activation of Sox4 is sufficient to induce the expression of N-cadherin and additional mesenchymal markers including vimentin and fibronectin, but fails to induce complete EMT as no changes are observed in the expression of E-cadherin and b-catenin. Moreover, shRNA-mediated knockdown of SOX4 significantly delays TGF-b-induced mRNA and protein expression of mesenchymal markers. Taken together, these data suggest that TGF-b-mediated increased expression of SOX4 is required for the induction of a mesenchymal phenotype during EMT in human mammary epithelial cells.
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