The discovery of the Janus kinase (JAK)-signal transducer and activator of transcripton (STAT) signaling pathway, a landmark in cell biology, provided a simple mechanism for gene regulation that ...dramatically advanced our understanding of the action of hormones, interferons, colony-stimulating factors, and interleukins. As we learn more about the complexities of immune responses, new insights into the functions of this pathway continue to be revealed, aided by technology that permits genome-wide views. As we celebrate the 20th anniversary of the discovery of this paradigm in cell signaling, it is particularly edifying to see how this knowledge has rapidly been translated to human immune disease. Not only have genome-wide association studies demonstrated that this pathway is highly relevant to human autoimmunity, but targeting JAKs is now a reality in immune-mediated disease.
Acute graft-versus-host disease (GvHD) is a major cause of mortality in allogeneic bone marrow transplantation (BMT), for which administration of FoxP3+ regulatory T (Treg) cells has been proposed as ...a therapy. However, the phenotypic stability of Treg cells is controversial, and STAT3-dependent cytokines can inhibit FoxP3 expression. We assessed whether the elimination of STAT3 in T cells could limit the severity of GvHD. We found STAT3 limited FoxP3+ Treg cell numbers following allogeneic BMT by two pathways: instability of natural Treg (nTreg) cells and inhibition of induced Treg (iTreg) cell polarization from naive CD4+ T cells. Deletion of STAT3 within only the nTreg cell population was not sufficient to protect against lethal GvHD. In contrast, transfer of STAT3-deficient naive CD4+ T cells increased FoxP3+ Treg cells post-BMT and prevented lethality, suggesting that the consequence of STAT3 signaling may be greater for iTreg rather than nTreg cells during GvHD.
► Acute graft versus host disease requires the presence of T cell STAT3 ► Transferred nTreg cells are unstable in the setting of acute GvHD ► Loss of nTreg cell FoxP3 expression in acute GvHD is largely dependent on STAT3 ► STAT3-deficient, but not wild-type, naive T cells become iTreg cells during acute GvHD
Follicular helper T (Tfh) cells comprise an important subset of helper T cells; however, their relationship with other helper lineages is incompletely understood. Herein, we showed interleukin-12 ...acting via the transcription factor STAT4 induced both
Il21 and
Bcl6 genes, generating cells with features of both Tfh and Th1 cells. However, STAT4 also induced the transcription factor T-bet. With ChIP-seq, we defined the genome-wide targets of T-bet and found that it repressed
Bcl6 and other markers of Tfh cells, thereby attenuating the nascent Tfh cell-like phenotype in the late phase of Th1 cell specification. Tfh-like cells were rapidly generated after
Toxoplasma gondii infection in mice, but T-bet constrained Tfh cell expansion and consequent germinal center formation and antibody production. Our data argue that Tfh and Th1 cells share a transitional stage through the signal mediated by STAT4, which promotes both phenotypes. However, T-bet represses Tfh cell functionalities, promoting full Th1 cell differentiation.
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► STAT4 drives
Il21 and
Bcl6 genes to create a cell with Tfh and Th1 cell features ► IFN-γ and T-bet attenuates the Tfh cell-like phenotype at later stage of the specification ► The
Bcl6 locus remains accessible in fully polarized Th1 cells ► T-bet limits Tfh and germinal center B cell generation during
T. gondii infection
Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling ...module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs. Here we review recent advances in Jak-STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.
The four Janus kinase (JAK) proteins and seven signal transducer and activator of transcription (STAT) transcription factors mediate intracellular signal transduction downstream of cytokine ...receptors, which are implicated in the pathology of autoimmune, allergic and inflammatory diseases. Development of targeted small-molecule therapies such as JAK inhibitors, which have varied selective inhibitory profiles, has enabled a paradigm shift in the treatment of diverse disorders. JAK inhibitors suppress intracellular signalling mediated by multiple cytokines involved in the pathological processes of rheumatoid arthritis and many other immune and inflammatory diseases, and therefore have the capacity to target multiple aspects of those diseases. In addition to rheumatoid arthritis, JAK inhibition has potential for treatment of autoimmune diseases including systemic lupus erythematosus, spondyloarthritis, inflammatory bowel disease and alopecia areata, in which stimulation of innate immunity activates adaptive immunity, leading to generation of autoreactive T cells and activation and differentiation of B cells. JAK inhibitors are also effective in the treatment of allergic disorders, such as atopic dermatitis, and can even be used for the COVID-19-related cytokine storm. Mechanism-based treatments targeting JAK-STAT pathways have the potential to provide positive outcomes by minimizing the use of glucocorticoids and/or non-specific immunosuppressants in the treatment of systemic immune-mediated inflammatory diseases.
The discovery of cytokines as key drivers of immune-mediated diseases has spurred efforts to target their associated signalling pathways. Janus kinases (JAKs) are essential signalling mediators ...downstream of many pro-inflammatory cytokines, and small-molecule inhibitors of JAKs (jakinibs) have gained traction as safe and efficacious options for the treatment of inflammation-driven pathologies such as rheumatoid arthritis, psoriasis and inflammatory bowel disease. Building on the clinical success of first-generation jakinibs, second-generation compounds that claim to be more selective are currently undergoing development and proceeding to clinical trials. However, important questions remain about the advantages and limitations of improved JAK selectivity, optimal routes and dosing regimens and how best to identify patients who will benefit from jakinibs. This Review discusses the biology of jakinibs from a translational perspective, focusing on recent insights from clinical trials, the development of novel agents and the use of jakinibs in a spectrum of immune and inflammatory diseases.
Recent work has identified a new subset of effector T cells that produces interleukin (IL)-17 known as T helper 17 (Th17) cells, which is involved in the pathophysiology of inflammatory diseases and ...is thought to be developmentally related to regulatory T (Treg) cells. Because of its importance for Treg cells, we examined the role of IL-2 in Th17 generation and demonstrate that a previously unrecognized aspect of IL-2 function is to constrain IL-17 production. Genetic deletion or antibody blockade of IL-2 promoted differentiation of the Th17 cell subset. Whereas STAT3 appeared to be a key positive regulator of RORγt and IL-17 expression, absence of IL-2 or disruption of its signaling by deletion of the transcription factor STAT5 resulted in enhanced Th17 cell development. We conclude that in addition to the promotion of activation-induced cell death of lymphocytes and the generation of Treg cells, inhibition of Th17 polarization appears to be an important function of IL-2.
CD4⁺ T cells are critical for host defense but are also major drivers of immune-mediated disease. These T cells specialize to become distinct subsets and produce restricted patterns of cytokines, ...which are tailored to combat various microbial pathogens. Although classically viewed as distinct lineages, recent work calls into question whether helper CD4⁺ T cell subsets are more appropriately viewed as terminally differentiated cells or works in progress. Herein, we review recent advances that pertain to this topic and the mechanisms that contribute to helper CD4⁺ T cell commitment and plasticity. The therapeutic implications of these new findings are also considered.
Signaling pathways are intimately involved in cellular differentiation, allowing cells to respond to their environment by regulating gene expression. Although enhancers are recognized as key elements ...that regulate selective gene expression, the interplay between signaling pathways and actively used enhancer elements is not clear. Here, we use CD4+ T cells as a model of differentiation, mapping the activity of cell-type-specific enhancer elements in T helper 1 (Th1) and Th2 cells. Our data establish that STAT proteins have a major impact on the activation of lineage-specific enhancers and the suppression of enhancers associated with alternative cell fates. Transcriptome analysis further supports a functional role for enhancers regulated by STATs. Importantly, expression of lineage-defining master regulators in STAT-deficient cells fails to fully recover the chromatin signature of STAT-dependent enhancers. Thus, these findings point to a critical role of STATs as environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells.
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► Closely related T helper cell subsets have distinct p300 binding profiles ► STATs activate lineage-specific enhancers and suppress those of alternative fates ► Overexpression of master regulators cannot compensate for lack of STATs ► Changes in T cell transcriptome correspond to changes in p300 binding
Responding to environmental cues, STAT proteins direct the establishment of enhancer signatures that promote unique T cell fates. Surprisingly, T cell master regulators cannot compensate for the lack of STATs, suggesting that STATs play an essential and independent role in the activation of lineage-specific enhancers.
The discovery of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway arose from investigations of how cells respond to interferons (IFNs), revealing a paradigm in ...cell signaling conserved from slime molds to mammals. These discoveries revealed mechanisms underlying rapid gene expression mediated by a wide variety of extracellular polypeptides including cytokines, interleukins, and related factors. This knowledge has provided numerous insights into human disease, from immune deficiencies to cancer, and was rapidly translated to new drugs for autoimmune, allergic, and infectious diseases, including COVID-19. Despite these advances, major challenges and opportunities remain.
The JAK/STAT pathway regulates multiple cellular processes across organisms. Molecular details of signaling mechanisms have revealed insights into a range of human diseases.
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