The evolutionally conserved transforming growth factor β (TGFβ) affects multiple cell types in the immune system by either stimulating or inhibiting their differentiation and function. Studies using transgenic mice with ablation of TGFβ or its receptor have revealed the biological significance of TGFβ signaling in the control of T cells. However, it is now clear that TGFβ is more than an immunosuppressive cytokine. Disruption of TGFβ signaling pathway also leads to impaired generation of certain T cell populations. Therefore, in the normal physiological state, TGFβ actively maintains T cell homeostasis and regulates T cell function. However, in the tumor microenvironment, TGFβ creates an immunosuppressive milieu that inhibits antitumor immunity. Here, we review recent advances in our understanding of the roles of TGFβ in the regulation of T cells and tumor immunity.
The interferons (IFNs) are glycoproteins with strong antiviral activities that represent one of the first lines of host defense against invading pathogens. These proteins are classified into three groups, Type I, II and III IFNs, based on the structure of their receptors on the cell surface. Due to their ability to modulate immune responses, they have become attractive therapeutic options to control chronic virus infections. In combination with other drugs, Type I IFNs are considered a “standard of care” in suppressing Hepatitis C (HCV) and Hepatitis B (HBV) infections, while Type III IFN has generated encouraging results as a treatment for HCV infection in phase III clinical trials. However, though effective, using IFNs as a treatment is not without the need for caution. IFNs are such powerful cytokines that affect a wide array of cell types; as a result, patients usually experience unpleasant symptoms, with a percentage of patients suffering system wide effects. Thus, constant monitoring is required for patients treated with IFN in order to reach the treatment goals of suppressing virus infection and maintaining quality of life.
Antiviral therapy; IFN-α/β; IFN-γ; IFN-λ
B cell-activating factor belonging to the TNF family (BAFF) exerts its pathogenic role in supporting the survival and proliferation of B cells, regulating class switch recombination as well as the selection of autoreactive B cells. Overexpression of BAFF induces a dramatic expansion of activated B cells, particularly marginal zone B cells, as well as hypergammaglobulinemia, autoantibody production and immune complex deposition. However, in addition to its effect on B cells, recent work has also demonstrated that BAFF can promote T cell activation, proliferation and differentiation. In this review, we have discussed the recent progress on the function and role of BAFF on T cells and T cell-mediated diseases.
BAFF; T helper cells; Th17; Tfh cells; Treg cells
The interferon-inducible p200 family comprises a group of homologous mouse and human proteins. Most of these have an N-terminal DAPIN domain and one or two partially conserved, 200 amino acid long C-terminal domains (designated as 200X domain). These proteins play important roles in the regulation of cell proliferation, tissue differentiation, apoptosis and senescence. p200 family proteins are involved also in autoimmunity and the control of tumor growth. These proteins function by binding to various target proteins (e.g. transcription factors, signaling proteins, oncoproteins and tumor suppressor proteins) and modulating target activity. This review concentrates on p204, a murine member of the family and its roles in regulating cell proliferation, cell and tissue differentiation (e.g. of skeletal muscle myotubes, beating cardiac myocytes, osteoblasts, chondrocytes and macrophages) and signaling by Ras proteins. The expression of p204 in various tissues as promoted by tissue-specific transcription factors, its distribution among subcellular compartments, and the controls of these features are also discussed.
p204; p200 (Ifi-200/Hin-200) family; Interferon; Cell proliferation; Differentiation
TRAF3 is an adapter protein that serves and regulates the functions of several types of receptors, located both inside the cell and at the plasma membrane. These include members of the TNF receptor superfamily (TNFR-SF), toll-like receptors (TLR), and cytokine receptors. It has become increasingly evident that the roles and functions of TRAF3 are highly context-dependent. TRAF3 can serve distinct roles for different receptors in the same cell, and also has highly cell-type-dependent functions. This review focuses upon the current state of knowledge regarding how TRAF3 regulates the biology and effector functions of B and T lymphocytes, two major cell types of the adaptive immune response in which TRAF3 has markedly distinct roles.
TRAF; B lymphocyte; T lymphocyte; signal transduction; lymphocyte activation
The lymphotoxin (LT)-pathway is a unique constituent branch of the Tumor Necrosis Superfamily (TNFSF). Use of LT is a critical mechanism by which fetal innate lymphoid cells regulate lymphoid organogenesis. Within recent years, adult innate lymphoid cells have been discovered to utilize this same pathway to regulate IL-22 and IL-23 production for host defense. Notably, genetic studies have linked polymorphisms in the genes encoding LTα to several phenotypes contributing to metabolic syndrome. The role of the LT-pathway may lay the foundation for a bridge between host immune response, microbiota, and metabolic syndrome. The contribution of the LT-pathway to innate lymphoid cell function and metabolic syndrome will be visited in this review.
Lymphotoxin; Innate Lymphoid Cells; Host defense; IL-22; IL-23; NK development; Metabolic Syndrome; Microbiota
It is now widely accepted that some forms of necrosis are controlled by a dedicated signaling pathway triggered by various cell surface and intracellular receptors. This regulated form of necrosis is mediated by the kinase activity of receptor-interacting protein kinase 1 (RIP1/RIPK1) and/or RIP3/RIPK3. A number of studies using the RIP1 kinase inhibitor Necrostatin-1 (Nec-1) and its derivatives, or RIP3-deficient mice demonstrated that RIP1 and RIP3 are involved in various infectious and sterile inflammatory diseases. As a consequence, these specific phenotypes were construed to depend on necrosis. However, emerging evidence indicates that the RIP1 kinase activity and RIP3 can also control apoptosis and inflammatory cytokine production independent of necrosis. Therefore, we may need to re-interpret conclusions drawn based on loss of RIP1 or RIP3 functions in in vivo models. We propose that studies of RIP1 and RIP3 in different inflammatory responses need to consider cell death-dependent and independent mechanisms of the RIP kinases.
RIP3/RIPK3; RIP1/RIPK1; Programmed Necrosis; Necroptosis; necrostatin-1; necrosome; apoptosis; NF-κB; Inflammasome; Inflammation; TNF; caspase 8; Fadd; MLKL; Pgam5
BLyS family members govern selection and survival of cells in the preimmune B cell compartment, and emerging evidence suggests similar roles in antigen-experienced B cell pools. We review the features of this family, with particular emphasis on recent findings of how BLyS influences affinity maturation in germinal centers, which lie at the intersection of the pre-immune and antigen-experienced B cell compartments. We propose a model whereby tolerogenic selection at the transitional stage and affinity maturation in the germinal center employ the same BLyS driven mechanism.
BLyS; BAFF; TACI; germinal center
TNF-like weak inducer of apoptosis (TWEAK), a TNF superfamily ligand, and its bona fide receptor, the TNF receptor superfamily member fibroblast growth factor-inducible protein 14 (Fn14), represents a pivotal axis for shaping both physiological and pathological tissue responses to acute or chronic injury and disease. In recent years significant advances have been made in delineating the prominent role of this axis in regulating skeletal muscle mass and metabolism. Also emerging from the broad study of tissue injury in skeletal muscle and other organs is the role of the TWEAK-Fn14 pathway in promoting fibrosis. This review article highlights recent advancements towards understanding how the TWEAK-Fn14 pathway regulates the response to various skeletal muscle insults and more broadly, engages multiple mechanisms to drive tissue fibrosis.
Skeletal muscle atrophy; Regeneration; NF-kappa B; Tissue injury; Fibrosis
The journey from the discoveries of lymphotoxin (LT) and tumor necrosis factor (TNF) to the present day age of cytokine inhibitors as therapeutics has been an exciting one with many participants and highs and lows; the saga is compared to that in “The Wizard of Oz”. This communication summarizes the contributions of key players in the discovery of the cytokines and their receptors, the changes in nomenclature, and the discovery of the LT family’s crucial role in secondary and tertiary lymphoid organs. The remarkable advances in therapeutics are detailed as are remaining problems. Finally, special tribute is paid to two pioneers in the field who have recently passed away: Byron H. Waksman and Lloyd Old.
The Wizard of Oz; Lymphotoxin; Tumor necrosis factor; Secondary lymphoid organs; Tertiary lymphoid organs; Therapeutic inhibitors of LT and TNF; Byron H. Waksman; Lloyd Old
The Lymphotoxin (LT) pathway is best known for its role in orchestrating the development and homeostasis lymph nodes and Peyer's patch through the regulation of homeostatic chemokines. More recently an appreciation of the LT! R pathway in the production of Type I interferons (IFN-I) during homeostasis and infection has emerged. LT! R signaling is essential in differentiating stromal cells and macrophages in lymphoid organs to rapidly produce IFN-I in response to virus infections independently of the conventional TLR signaling systems. In addition, LT! R signaling is required to produce homeostatic levels of IFN-I from dendritic cells in order to effectively cross-prime a CD8+ T cell response to protein antigen. Importantly, pharmacological inhibition of LT! R signaling in mice has a profound positive impact on a number of autoimmune disease models, although it remains unclear if this efficacy is linked to IFN-I production during chronic inflammation. In this review, we will provide a brief overview of how the “Lymphotoxin Network” is linked to the IFN-I response and its impact on the immune system.
Autoimmunity; cytokines; dendritic cells; Interferon (IFN); Lymphotoxin-! ! !(LT! ! ); stromal cells
Interleukin 27 (IL-27) is an immunomodulatory cytokine with important roles in both the innate and adaptive immune systems. In the last five years, the addition of exogenous IL-27 to primary cell cultures has been demonstrated to decrease HIV-1 replication in a number of cell types including peripheral blood mononuclear cells (PBMCs), CD4+ T cells, macrophages and dendritic cells. These in-vitro findings suggest that IL-27 may have therapeutic value in the setting of HIV-1 infection. In this review, we describe the current knowledge of the biology of IL-27, its effects primarily on HIV-1 replication but also in other viral infections and explore its potential role as a therapeutic cytokine for the treatment of patients with HIV-1 infection.
Interleukin-27; HIV; cytokines; SPTBN1; therapy
STING has emerged in recent years as an important signalling adaptor in the activation of type I interferon responses during infection with DNA viruses and bacteria. An increasing body of evidence suggests that STING also modulates responses to RNA viruses, though the mechanisms remain less clear. In this review, we give a brief overview of the ways in which STING facilitates sensing of RNA viruses. These include modulation of RIG-I-dependent responses through STING's interaction with MAVS, and more speculative mechanisms involving the DNA sensor cGAS and sensing of membrane remodelling events. We then provide an in-depth literature review to summarise the known mechanisms by which RNA viruses of the families Flaviviridae and Coronaviridae evade sensing through STING. Our own work has shown that the NS2B/3 protease complex of the flavivirus dengue virus binds and cleaves STING, and that an inability to degrade murine STING may contribute to host restriction in this virus. We contrast this to the mechanism employed by the distantly related hepacivirus hepatitis C virus, in which STING is bound and inactivated by the NS4B protein. Finally, we discuss STING antagonism in the coronaviruses SARS coronavirus and human coronavirus NL63, which disrupt K63-linked polyubiquitination and dimerisation of STING (both of which are required for STING-mediated activation of IRF-3) via their papain-like proteases. We draw parallels with less-well characterised mechanisms of STING antagonism in related viruses, and place our current knowledge in the context of species tropism restrictions that potentially affect the emergence of new human pathogens.
BiFC, bimolecular fluorescence complementation; CARD, caspase activation and recruitment domain; cGAMP, cyclic GMP-AMP; cGAS, cyclic GMP-AMP synthase; DC, dendritic cell; DUB, deubiquitinase; hSTING, human STING; IFN, interferon; IRF-3, interferon regulatory factor 3; ISG, interferon-stimulated gene; ISRE, interferon-stimulated response element; MAM, mitochondria-associated membrane; MAVS, mitochondrial antiviral signalling protein; MDA-5, melanoma differentiation-associated gene 5; MDDC, monocyte-derived dendritic cell; mKG, monomeric Kusabira Green; mSTING, murine STING; PBMC, peripheral blood mononuclear cells; PI(3)K, phosphatidylinositol-3-OH kinase; PLP, papain-like protease; PLpro, papain-like protease; RIG-I, retinoic acid-inducible gene I; STAT2, signal transducer and activator of transcription 2; STING, stimulator of interferon genes; TBK1, tank-binding kinase 1; TRIM32, tripartite motif-containing 32; TRIM56, tripartite motif-containing 56; STING; Immune evasion; Dengue; Hepatitis C virus; SARS coronavirus
Pre-B cell colony enhancing factor (PBEF) is regarded as a proinflammatory cytokine. Named for its first discovered function as a pre-B cell colony enhancing factor, it has since been found to have many other functions relating to cell metabolism, inflammation, and immune modulation. It has also been found to have intracellular and extracellular forms, with the two overlapping in function. Most of the intracellular functions of PBEF are due to its role as a nicotinamide phosphoribosyltransferase (Nampt). It has been found in human endothelial cells, where it is able to induce angiogenesis through upregulation of VEGF and VEGFR and secretion of MCP-1. In human umbilical endothelial cells, PBEF increases levels of the protease MMP 2/9. PBEF has also been found in a variety of immune cells other than B cells and has been shown to inhibit apoptosis of macrophages. Extracellular PBEF has been shown to increase inflammatory cytokines, such as TNF-α, IL-1β, IL-16, and TGF-β1, and the chemokine receptor CCR3. PBEF also increases the production of IL-6, TNF-α, and IL-1β in CD14+ monocyctes, macrophages, and dendritic cells, enhances the effectiveness of T cells, and is vital to the development of both B and T lymphocytes. The purpose of this review is to summarize the recent advances in PBEF research.
pre-B cell enhancing factor; cytokine; chemikine; monocyte; B lymphocyte; T lymphocyte
Although chemokines are well established to function in immunity and endothelial cell activation and proliferation, a rapidly growing literature suggests that CXC Chemokine receptors CXCR3, CXCR4 and CXCR7 are critical in the development and progression of solid tumors. The effect of these chemokine receptors in tumorigenesis is mediated via interactions with shared ligands I-TAC (CXCL11) and SDF-1 (CXCL12). Over the last decade, CXCR4 has been extensively reported to be overexpressed in most human solid tumors and has earned considerable attention toward elucidating its role in cancer metastasis. To enrich the existing armamentarium of anti-cancerous agents, many inhibitors of CXCL12–CXCR4 axis have emerged as additional or alternative agents for neoadjuvant treatments and even many of them are in preclinical and clinical stages of their development. However, the discovery of CXCR7 as another receptor for CXCL12 with rather high binding affinity and recent reports about its involvement in cancer progression, has questioned the potential of “selective blockade” of CXCR4 as cancer chemotherapeutics. Interestingly, CXCR7 can also bind another chemokine CXCL11, which is an established ligand for CXCR3. Recent reports have documented that CXCR3 and their ligands are overexpressed in different solid tumors and regulate tumor growth and metastasis. Therefore, it is important to consider the interactions and crosstalk between these three chemokine receptors and their ligand mediated signaling cascades for the development of effective anti-cancer therapies. Emerging evidence also indicates that these receptors are differentially expressed in tumor endothelial cells as well as in cancer stem cells, suggesting their direct role in regulating tumor angiogenesis and metastasis. In this review, we will focus on the signals mediated by this receptor trio via their shared ligands and their role in tumor growth and progression.
CXC chemokines; Tumor growth; Angiogenesis; Metastasis
TGFβ is secreted in a latent state and must be
“activated” by molecules that facilitate its release from a
latent complex and allow binding to high affinity cell surface receptors.
Numerous molecules have been implicated as potential mediators of this
activation process, but only a limited number of these activators have been
demonstrated to play a role in TGFβ mobilization in
vivo. Here we review the process of TGFβ secretion and
activation using evolutionary data, sequence conservation and structural
information to examine the molecular mechanisms by which TGFβ is
secreted, sequestered and released. This allows the separation of more ancient
TGFβ activators from those factors that emerged more recently, and helps
to define a potential hierarchy of activation mechanisms.
TGFbeta; activation; evolution; LTBP; Extracellular matrix
The CBM signalosome plays a pivotal role in mediating antigen-receptor induced NF-κB signaling to regulate lymphocyte functions. The CBM complex forms filamentous structure and recruits downstream signaling components to activate NF-κB. MALT1, the protease component in the CBM complex, cleaves key proteins in the feedback loop of the NF-κB signaling pathway and enhances NF-κB activation. The aberrant activity of the CBM complex has been linked to aggressive lymphoma. Recent years have witnessed dramatic progresses in understanding the assembly mechanism of the CBM complex, and advances in the development of targeted therapy for aggressive lymphoma. Here, we will highlight these progresses and give an outlook on the potential translation of this knowledge from bench to bedside for aggressive lymphoma patients.
CBM complex; Lymphoma; NF-κB; Targeted therapy
Latently infected resting CD4+ T cells are the major barrier to curing HIV. We have recently demonstrated that chemokines, which bind to the chemokine receptors CCR7, CXCR3 and CCR6, facilitate efficient HIV nuclear localisation and integration in resting CD4+ T cells, leading to latency. As latently infected cells are enriched in lymphoid tissues, where chemokines are highly concentrated, this may provide a mechanism for the generation of latently infected cells in vivo. Here we review the role of chemokines in HIV persistence; the main signalling pathways that are involved; and how these pathways may be exploited to develop novel strategies to reduce or eliminate latently infected cells.
Human immunodeficiency virus (HIV); Chemokine; Signalling; Latency; Persistence
This review focuses on contributions to cytokine biology made by Australians in Australia. It is clearly biased by my own experiences and selective recollections especially related to the colony-stimulating factors in which Australian involvement has been pre-eminent from discovery to clinical use. Nevertheless Australian scientists have also made profound contributions to other areas of cytokine and growth factor biology (including interferons, inflammatory cytokines, chemokines and epidermal, insulin-like and vascular endothelial growth factors) that are briefly described in this review as well as other chapters in this volume.
The discovery of the Suppressor Of Cytokine Signaling (SOCS) family of proteins has resulted in a significant body of research dedicated to dissecting their biological functions and the molecular mechanisms by which they achieve potent and specific inhibition of cytokine and growth factor signaling. The Australian contribution to this field has been substantial, with the initial discovery of SOCS1 by Hilton, Starr and colleagues (discovered concurrently by two other groups) and the following work, providing a new perspective on the regulation of JAK/STAT signaling. In this review, we reflect on the critical discoveries that have lead to our current understanding of how SOCS proteins function and discuss what we see as important questions for future research.
SOCS; SOCS box; cytokine; receptor; JAK
Interleukin-22 (IL-22) is an IL-10 family cytokine member that was recently discovered to be mainly produced by Th17 cells. Previous studies have indicated the importance of IL-22 in host defense against Gram-negative bacterial organisms (in gut and lung). Recently, there is emerging evidence that IL-22 is involved in the development and pathogenesis of several autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Sjögren’s syndrome (SS) and psoriasis. Therapeutics targeting IL-22 therefore may have promise for treating various autoimmune diseases. In this review, we discuss the recent progression of the involvement of IL-22 in the development and pathogenesis of autoimmune diseases, as well as its clinical implications and therapeutic potential.
IL-22; Th17; Th22; autoimmune; therapeutic
The Snail/Gfi-1 (SNAG) family of zinc finger proteins is a group of transcriptional repressors that have been intensively studied in mammals. SNAG family members are similarly structured with an N-terminal SNAG repression domain and a C-terminal zinc finger DNA binding domain, however, the spectrum of target genes they regulate and the ranges of biological functions they govern vary widely between them. They play active roles in transcriptional regulation, formation of repressive chromatin structure, cellular signaling and developmental processes. They can also result in disease states due to deregulation. We have performed a thorough investigation of the relevant literature and present a comprehensive mini-review. Based on the available information, we also propose a mechanism by which SNAG family members may function.
SNAG repression domain; SNAG-ZFP target genes; Transcription Regulation; Cellular signaling and Development; EMT and Cancer
Mycobacterium tuberculosis (Mtb) is the intracellular pathogen that causes the disease, tuberculosis. Chemokines and chemokine receptors are key regulators in immune cell recruitment to sites of infection and inflammation. This review highlights our recent advances in understanding the role of chemokines and chemokine receptors in cellular recruitment of immune cells to the lung, role in granuloma formation and host defense against Mtb infection.
Tuberculosis; Chemokines; lung
Although the causes of inflammatory arthritis elude us, aberrant cytokine expression has been linked to joint pathology. Consequently, several approaches in the clinic and/or in clinical trials are targeting cytokines, e.g. tumor necrosis factor (TNF), interleukin 23 (IL-23) and interleukin 17 (IL-17), with the goal of antagonizing their respective biologic activity through therapeutic neutralizing antibodies. Such, cytokine signaling-dependent molecular networks orchestrate synovial inflammation on multiple levels including differentiation of myeloid cells to osteoclasts, the central cellular players in arthritis-associated pathologic bone resorption. Hence, understanding of the cellular and molecular mechanisms elicited by synovial cytokine networks that dictate recruitment, differentiation and activation of osteoclast precursors and osteoclasts, respectively, is central to shaping novel therapeutic options for inflammatory arthritis patients. In this article we are discussing the complex signaling interactions involved in the regulation of inflammatory arthritis and it’s associated bone loss with a focus on interleukin 27 (IL-27). The present review will discuss the primary bone-degrading cell, the osteoclast, and on how IL-27, directly or indirectly, modulates osteoclast activity in autoimmune-driven inflammatory joint diseases.