Modulation of immune responses through direct activation of Toll‐like receptors to T cells

Toll‐like receptors (TLRs), which are a family of pattern recognition receptors (PRRs), are involved critically in the generation and regulation of innate immunity as well as initiation of subsequent adaptive immune responses. However, recent research results showed that different subsets of T cells express certain types of TLRs during development and activation stages. Importantly, TLRs participate in the direct regulation of adaptive immune response, possibly as co‐stimulatory molecules. In this review we summarize recent studies about the novel regulation of TLRs on the homeostasis and immunity of different T cell subtypes including CD4⁺CD25⁺T regulatory cells (T_reg) and interleukin (IL)‐17‐producing CD4⁺T cells (T helper type 17). The direct involvement of TLRs in T cell‐mediated immunity prompted us to reconsider the role of TLRs in the occurrence of autoimmune diseases, infectious diseases and graft rejection. The important effects of TLRs in T cell‐intrinsic components also prompt us to explore novel vaccine adjuvants for modifying desired immune responses in an efficient way.     

The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice

Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors that are essential for host immune responses. TLR ligands represent a promising class of immunotherapeutics or vaccine adjuvants with the potential to generate an effective antitumor immune response. The TLR7/8 agonists have aroused interest because they not only activate antigen-presenting cells but also promote activation of T and natural killer (NK) cells. However, the exact mechanism by which stimulation of these TLRs promotes immune responses remains unclear, and different TLR7/8 agonists have been found to induce different responses. In this study, we demonstrate that both gardiquimod and imiquimod promote the proliferation of murine splenocytes, stimulate the activation of splenic T, NK and natural killer T (NKT) cells, increase the cytolytic activity of splenocytes against B16 and MCA-38 tumor cell lines, and enhance the expression of costimulatory molecules and IL-12 by macrophages and bone marrow-derived dendritic cells (DCs). In a murine model, both agonists improved the antitumor effects of tumor lysate-loaded DCs, resulting in delayed growth of subcutaneous B16 melanoma tumors and suppression of pulmonary metastasis. Further, we found that gardiquimod demonstrated more potent antitumor activity than imiquimod. These results suggest that TLR7/8 agonists may serve as potent innate and adaptive immune response modifiers in tumor therapy. More importantly, they can be used as vaccine adjuvants to potentiate the efficiency of DC-based tumor immunotherapy.     

Roles of toll-like receptors in natural interferon-producing cells as sensors in immune surveillance

Natural IFN-alpha/beta producing cells (IPCs) play a central role in innate immunity against microbial infections. In primary immune responses, toll-like receptors (TLRs), as major pattern-recognition receptors, are essential for IPCs as well as other antigen presenting cell (APC) subsets to recognize microbes. IPCs unequivocally express TLR7 and TLR9, and can respond to the respective ligand to produce IFN-alpha/beta and to rapidly differentiate into dendritic cells (DCs). Thereby, IPCs can not only activate innate immune system but also provoke T cell responses. Thus, IPCs link innate and adaptive immunity through TLR system. In addition, recent work has revealed the regulatory system of DC subsets in response to microbial invasion. In this context, by the different but complementary expression profile of TLRs, IPCs together with myeloid APC subsets constitute a rational system of immune surveillance that can cover a wide variety of pathogens and enlarge immune adjuvant effects.     

Toll-like receptors and innate immunity

The innate immune system is an evolutionally conserved host defense mechanism against pathogens. Innate immune responses are initiated by pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Among them, Toll-like receptors (TLRs) are capable of sensing organisms ranging from bacteria to fungi, protozoa, and viruses, and play a major role in innate immunity. However, TLRs recognize pathogens either on the cell surface or in the lysosome/endosome compartment. Recently, cytoplasmic PRRs have been identified to detect pathogens that have invaded cytosols. In this review, we focus on the functions of PRRs in innate immunity and their downstream signaling cascades.     

Pathogens use carbohydrates to escape immunity induced by dendritic cells

Dendritic cells (DCs) play a central role in balancing immune responses between tolerance induction and immune activation. Under steady state conditions DCs continuously sample antigens, leading to tolerance, whereas inflammatory conditions activate DCs, inducing immune activation. DCs express C-type lectin receptors (CLRs) for antigen capture and presentation, whereas Toll-like receptors (TLRs) are involved in pathogen recognition and DC activation. Recent data demonstrate that communication between TLRs and CLRs can affect the direction of immune responses. Several pathogens specifically target CLRs to subvert this communication to escape immune surveillance, either by inducing tolerance or skewing the protective immune responses.     

Toll-like receptors and immune response in allergic disease

Allergic reactions are dominated by the preferential development of specific Th2 responses against innocuous antigens in atopic individuals. This can reflect alterations in innate immune mechanisms. Toll-like receptors (TLRs) have evolved as key molecules., in innate and adaptive immunity. Their activation by structurally distinct exogenous or endogenous, ligands present at the cell microenvironment plays a critical role in antimicrobial defense. The global view is that TLR activation induces antigen-presenting, cells to produce cytokines that favor Th1-type immune responses, suggesting that it might prevent the development of deleterious Th2 responses in allergy. On the basis of epidemiological studies and recent data, it has been established that TLRs play a role in the development of Th2 responses. However, more information is needed to fully understand the mechanism of TLR involvement and the implication of immune cells that express TLRs in the Th1/Th2 cytokine profiles. Several TLRs, such as TLR9, TLR7, and TLR8, can be considered as good target candidates. Some TLR ligands, such as CpG DNA, are effective adjuvants, strong inducers of both IL-5 and eosinophilia downregulation. They are also potential links to allergen epitopes that could provide new allergen-specific immunotherapy regimens for the treatment of allergic disorders.     

Toll‐like receptors: The role in bladder cancer development,progression and immunotherapy

Bladder cancer is one of the leading causes of death worldwide. The main immune mechanisms which lead to bladder cancer development or treatment outcomes have yet to be elucidated. Toll‐like receptors (TLRs) play key roles against cancer. TLRs are expressed both on immune cells and on tumour cells and drive immune responses in progression as well as treatment of cancer. Identification of signalling pathways via TLRs could revolutionize further improvement of therapeutic strategies against cancers in the future. According to the recent studies, TLRs agonists are effective immunostimulants and have important role in induction of immune responses with immunotherapeutic potential against several diseases including cancer. They play an important role in the bladder urothelium as a part of immune defence against uropathogens. On the other hand, decreased TLRs expression was found in bladder tumours, particularly in non‐muscle‐invasive ones. Bacillus Calmette‐Guerin (BCG) (agonist of TLR2 and TLR4) is approved by US FDA for immunotherapy of bladder cancer. Despite high efficiency, immunotherapy with BCG may cause toxicity and adverse effects. Nowadays, in vitro and in vivo studies have been conducted to find alternative options for non‐responder patients. Studies on TLR agonists for bladder cancer treatment have shown promising results. In this review, we discuss recent data about mechanisms played by TLRs in bladder cancer developments as well as therapeutic application of TLR agonists in cancer treatment.     

Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells

The innate immune system deploys a variety of pattern-recognition receptors (PRRs) which include Toll-like receptors (TLRs), RIG-I-like receptors, NOD-like receptors, and C-type lectin receptors to detect the invasion of pathogens and initiate protective responses. The intercellular and intracellular orchestration of signals from different PRRs, their endogenous or microbial ligands and accessory molecules determine the stimulatory or inhibitory responses. Progressing over the last two decades, considerable research on the molecular mechanisms underlying host–pathogen interactions has led to a paradigm shift of our understanding of TLR signaling in the innate immune system. Given that a significant amount of evidence implicates TLRs in the pathogenesis of immune diseases and cancer, and their activation occurs early in the inflammatory cascade, they are attractive targets for novel therapeutic agents. In this review, we discuss the recent advances in TLR signaling cross talks and the mechanism of pathogen recognition with special emphasis on the role of TLRs in tumor immunity and TLR-targeted therapeutics.     

Toll-like receptors in the skin

Toll-like receptors (TLRs) are important pattern-recognition receptors involved in host defense against a variety of pathogenic microorganisms. Activation of TLRs leads to the production of cytokines, chemokines, antimicrobial peptides, and upregulation costimulatory and adhesion molecules involved in innate and adaptive immune responses. TLRs are expressed on a variety of cell types found in the skin, including keratinocytes and Langerhans cells in the epidermis, resident and trafficking immune-system cells such as macrophages, dendritic cells, T and B cells, and mast cells in the dermis, endothelial cells of the skin microvasculature, and skin stromal cells such as fibroblasts and adipocytes. There have been an increasing number of reports demonstrating that TLRs play a key role in cutaneous host defense mechanisms against bacterial, fungal, and viral pathogens. In addition, TLRs have also been implicated in the pathophysiology of various inflammatory skin diseases.     

Toll样受体与肿瘤

Toll样受体的发现是近二十年整个医学领域的一项重大发现.Toll样受体作为先天免疫的重要组成部分,是一种模式识别受体.它通过识别病原相关分子模式在机体天然免疫应答中发挥重要作用.Toll样受体不仅仅表达在免疫细胞,同样也表达在肿瘤细胞,影响着肿瘤的发生、发展.Toll样受体激活可发挥抗肿瘤的作用,但也可促进肿瘤的进展.人们对这截然相反的结果的发生机制还了解甚少.Toll样受体还能识别损伤相关分子模式形成慢性炎症微环境影响肿瘤的发生、发展、治疗.本文对Toll样受体与肿瘤之间的关系及相应研究最新进展进行综述.     

TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance

Tumors actively develop different mechanisms such as immunosuppressive cytokine production to escape from immune control and limit the success of immunotherapy. More and more evidences suggest that chronic inflammation contributes to cancer development and progression. Recently, Toll-like receptors (TLRs), the receptors by which immune cells recognize microbial conserved components such as lipopolysaccharide (LPS) then initiate immune and inflammatory responses, have been found to be expressed by some kinds of tumor cells. However, what is the biological function of TLRs on tumor cells and whether human lung cancer cells can express TLRs remain to be fully understood. In the present study, we demonstrate that TLR4 is expressed on human lung cancer cell lines. TLR4 ligation promotes production of immunosuppressive cytokines TGF-beta, VEGF, proangiogenic chemokine IL-8 by human lung cancer cells. In addition, TLR4 ligation induces resistance of human lung cancer cells to TNF-alpha or TRAIL-induced apoptosis. Furthermore, we show p38MAPK activation is necessary for increased VEGF and IL-8 secretion, NF-kappaB activation contributes to apoptosis resistance of human lung cancer cells induced by LPS. Therefore, we demonstrate that TLR4 expressed on human lung cancer cells is functionally active, and may play important roles in promoting immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance.     

Cross-talk between pathogen recognizing Toll-like receptors and immunoglobulin Fc receptors in immunity

The individual role of pathogen-binding Toll-like receptors (TLRs) and antibody-binding Fc receptors (FcRs) during pathogenic infections has been studied extensively. However, combined activation of these different receptor classes has received little attention, even though they are triggered simultaneously when immune cells bind antibody-opsonized pathogens. In the last few years, it has become evident that joined activation of TLRs and FcRs substantially tailors inflammatory immune responses, which is an efficient and controlled mechanism of the host to act upon invading pathogens. In this review, we discuss the mechanisms of cross-talk between different TLRs and FcRs and the resulting inflammatory immune responses. Furthermore, we propose how chronic activation via this cross-talk might be detrimental in inflammatory (auto) immune diseases. We conclude with the potential exploitation of the interplay between TLRs and FcRs for monoclonal antibody therapy to target tumors. Future interests in this field of research include establishing a more detailed and mechanistic understanding of the mode of action of TLR and FcR cross-talk and exploration of its physiological importance in health and disease. This may furthermore open up novel therapeutic options for intervention in inflammatory diseases or cancer.     

Toll-like Receptor Signaling Pathways in Cardiovascular Diseases: Challenges and Opportunities

Toll-like receptors (TLRs), a family of surface molecules, are involved in innate immune responses. Recent studies indicated that TLRs play a critical role in inflammatory responses to exogenous and endogenous triggers. This article focuses on probable effects of TLRs in the morbidity of cardiovascular events, e.g., ischemic reperfusion (I/R) injury and atherosclerosis. TLR2 and TLR4 have been shown to have the most fundamental role in promoting cytokine production and subsequent inflammatory damages in these states. Blockade of these receptors may be beneficial in both preventing the occurrence and decreasing the complications in cardiovascular events. However, controversies exist on the certainty of this beneficial effect; therefore, additional studies are needed.     

Direct and indirect role of Toll-like receptors in T cell mediated immunity

Toll-like receptors (TLR) are pathogen-associated molecular patterns (PAMPs) recognition receptors that playan important role in protective immunity against infection and inflammation.They act as central integrators ofa wide variety of signals,responding to diverse agonists of microbial products.Stimulation of Toll-like receptorsby microbial products leads to signaling pathways that activate not only innate,but also adaptive immunity byAPC dependent or independent mechanisms.Recent evidence revealed that TLR signals played a determiningrole in the skewing of na(?)ve T cells towards either Th1 or Th2 responses.Activation of Toll-like receptors alsodirectly or indirectly influences regulatory T cell functions.Therefore,TLRs are required in both immuneactivation and immune regulation.Study of TLRs has significantly enhanced our understanding of innate andadaptive immune responses and provides novel therapeutic approaches against infectious and inflammatorydiseases.Cellular & Molecular Immunology.2004;1(4):239-246.     

Toll-like receptor (TLR) expression of immune system cells from metastatic breast cancer patients with circulating tumor cells

The risk posed by breast cancer represents a complex interaction among factors affecting tumor immunity of the host. Toll-like receptors (TLRs) are members of the innate immune system and generally function to attract host immune cells upon activation. However, the good intentions of TLRs are sometimes not transferred to positive long-term effects, due to their involvement in exacerbating inflammatory effects and even contributing to continued inflammation. Chronic inflammatory states are considered to favor an increased predisposition to cancer, with continuous activation of inflammatory cytokines and other hallmarks of inflammation exerting a deleterious effect. Circulating tumor cells (CTCs) are neoplastic cells present in the peripheral blood circulation that have been found to be an indicator of disease progression and long-term survival. In the present study, we examined the expression of TLRs on dendritic cells, which play a major role in eliciting anti-tumor immunity, in metastatic breast cancer patients with CTCs. Flow cytometric data showed significant differences between circulating tumor cell (CTC) positive patients and CTC negative patients in their expression of TLR2 by CD8 positive cytotoxic T cells and TLR2, TLR4, TLR3, and TLR8 by CD11c positive dendritic cells (p < 0.05). Expression of TLR2, TLR4, and TLR8 was increased in CTC positive patients, whereas TLR3 expression was decreased in the dendritic cell population.     

Toll样受体在机体抗病毒免疫反应中的作用

哺乳动物的Toll样受体(TLR)家族具有模式识别受体的功能,其可以识别微生物的保守分子成分,启动机体的固有免疫系统,从而帮助机体清除病原体.利用TLR敲除的动物或细胞模型进行的研究使人们认识到TLR在机体抗病毒免疫反应中发挥着重要作用.病毒与宿主细胞的TLR结合后,通过NF-κB或IRF-3的信号路径激活细胞因子的表达,从而激发免疫应答.研究TLR如何与病原体结合及如何激活下游基因对深入认识病原体所致相关疾病的发病机制、免疫应答及病理生理具有重要的意义,并为病毒性疾病的临床治疗或免疫预防提供新的思路.     

The role of toll-like receptors in systemic lupus erythematosus

Systemic lupus erythematosus is an autoimmune disease characterized by the production of autoantibodies against a relatively limited range of nuclear antigens. These autoantibodies result in the formation of immune complexes that deposit in tissues and induce inflammation, thereby contributing to disease pathology. Growing evidence suggests that recognition of nucleic acid motifs by Toll-like receptors may play a role in both the activation of antinuclear B cells and in the subsequent disease progression after immune complex formation. The endosomal localization of the nucleic acid-sensing Toll-like receptors (TLRs), TLR3, 7, and 9, is believed to contribute to the distinction between endogenous nucleic acids and those of foreign origin. In this article we review recent work that suggests a role for the B-cell receptor and Fcγ receptors in delivering nuclear antigens to intracellular compartments allowing TLR activation by endogenous nucleic acids. A number of in vitro studies have presented evidence supporting a role for TLRs in SLE pathology. However, recent studies that have examined the contributions of individual TLRs to SLE by using TLR-deficient mice suggest that the situation is far more complicated in vivo. These studies show that under different circumstances TLR signaling may either exacerbate or protect against SLE-associated pathology. Further understanding of the role of TLRs in pathological autoreactivity of the adaptive immune system will likely lead to important insights into the etiopathogenesis of SLE and potential targets for novel therapies.     

Activation of hepatic natural killer cells and control of liver-adapted lymphoma in the murine model of cytomegalovirus infection

Hematopoietic stem cell transplantation (HSCT) is a promising therapeutic option against hematopoietic malignancies. Infection with cytomegalovirus (CMV) and tumor relapse are complications that limit the success of HSCT. In theory, CMV infection can facilitate tumor relapse and growth by inhibiting “graft take” and reconstitution of the immune system or by inducing the secretion of tumor cell growth-promoting cytokines. Conversely, one can also envisage an anti-tumoral effect of CMV by cytopathic/oncolytic infection of tumor cells, by inducing the secretion of death ligands for tumor cell apoptosis, and by the activation of systemic innate and adaptive immunity. Here we will briefly review the current knowledge about tumor control in a murine model of CMV infection and liver-adapted B cell lymphoma, with a focus on a putative implication of CD49⁺NKG2D⁺ hepatic natural killer cells. There are inclusions in this text reproduced or recombined from previous articles published in the Journal of Virology (American Society for Microbiology), which are cited in the reference section.     

MicroRNAs in the regulation of TLR and RIG-I pathways

The innate immune system recognizes invading pathogens through germline-encoded pattern recognition receptors (PRRs), which elicit innate antimicrobial and inflammatory responses and initiate adaptive immunity to control or eliminate infection. Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) are the key innate immune PRRs and are tightly regulated by elaborate mechanisms to ensure a beneficial outcome in response to foreign invaders. Although much of the focus in the literature has been on the study of protein regulators of inflammation, microRNAs (miRNAs) have emerged as important controllers of certain features of the inflammatory process. Several miRNAs are induced by TLR and RIG-I activation in myeloid cells and act as feedback regulators of TLR and RIG-I signaling. In this review, we comprehensively discuss the recent understanding of how miRNA networks respond to TLR and RIG-I signaling and their role in the initiation and termination of inflammatory responses. Increasing evidence also indicates that both virus-encoded miRNAs and cellular miRNAs have important functions in viral replication and host anti-viral immunity.