Regulating the proinflammatory response to composite biomaterials by targeting immunometabolism

Composite biomaterials comprising polylactide(PLA)and hydroxyapatite(HA)are applied in bone,cartilage and dental regenerative medicine,where HA confers osteoconductive properties.However,after surgical implantation,adverse immune responses to these composites can occur,which have been attributed to size and morphology of HA particles.Approaches to effectively modulate these adverse immune responses have not been described.PLA degradation products have been shown to alter immune cell metabolism(immunometabolism),which drives the inflammatory response.Accordingly,to modulate the inflammatory response to composite biomaterials,inhibitors were incorporated into composites comprised of amorphous PLA(aPLA)and HA(aPLA+HA)to regulate glycolytic flux.Inhibition at specific steps in glycolysis reduced proinflammatory(CD86+CD206-)and increased pro-regenerative(CD206+)immune cell populations around implanted aPLA+HA.Notably,neutrophil and dendritic cell(DC)numbers along with proinflammatory monocyte and macrophage populations were decreased,and Arginase 1 expression among DCs was increased.Targeting immunometabolism to control the proinflammatory response to biomaterial composites,thereby creating a pro-regenerative microenvironment,is a significant advance in tissue engineering where immunomodulation enhances osseointegration and angiogenesis,which could lead to improved bone regeneration.

Bile acid coordinates microbiota homeostasis and systemic immunometabolism in cardiometabolic diseases

Cardiometabolic disease(CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids(BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor(FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.

Impact of intracellular innate immune receptors on immunometabolism

Immunometabolism,which is the metabolic reprogramming of anaerobic glycolysis,oxidative phosphorylation,and metabolite synthesis upon immune cell activation,has gained importance as a regulator of the homeostasis,activation,proliferation,and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity.Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection,inflammation,cancer,autoimmune diseases,and metabolic disorders.The crosstalk between the PI3K-AKT-mTOR and LKB1-AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism.The bidirectional interaction between immune cells and metabolism is a topic of intense study.Toll-like receptors(TLRs),cytokine receptors,and T and B cell receptors have been shown to activate multiple downstream metabolic pathways.However,how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood.The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors,such as nucleotide-binding and leucine-rich repeat-containing receptors(NLRs,or NOD-like receptors),absent in melanoma 2(AIM2)-like receptors(ALRs),and the cyclic dinucleotide receptor stimulator of interferon genes(STING).We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways.Whenever appropriate,this review will provide a brief contextual connection to pathogenic infections,autoimmune diseases,cancers,metabolic disorders,and/or inflammatory bowel diseases.

Targeting immunometabolism by active ingredients derived from traditional Chinese medicines for treatment of rheumatoid arthritis

Rheumatoid arthritis(RA),the most common inflammatory arthropathy word wild,is a systemic autoimmune disease that mainly affects the synovium of joints with a high disability rate.Metabolic misregulation has emerged as a fundamental pathogenesis of RA linked to immune cell dysfunction,while targeting immunometabolism provides a new and effective approach to regulate the immune responses and thus alleviate the symptom of RA.Recently,natural active compounds from traditional Chinese medicines(TCMs)have potential therapeutic effects on RA and regulating immunometabolism.In this review,in addition to updating the connection between cellular metabolism and cell function in immune cells of RA,we summarized that the anti-inflammatory mechanisms of the potential natural compounds from TCM by targeting metabolic reprogramming of immune cells,and discusses them as a rich resource for providing the new potential paradigm for the treatment of RA.

ACOD1 in immunometabolism and disease

Immunometabolism plays a fundamental role in health and diseases and involves multiple genes and signals.Aconitate decarboxylase 1(ACOD1;also known as IRG1)is emerging as a regulator of immunometabolism in inflammation and infection.Upregulation of ACOD1 expression occurs in activated immune cells(e.g.,macrophages and monocytes)in response to pathogen infection(e.g.,bacteria and viruses),pathogen-associated molecular pattern molecules(e.g.,LPS),cytokines(e.g.,TNF and IFNs),and damage-associated molecular patterns(e.g.,monosodium urate).Mechanistically,several immune receptors(e.g.,TLRs and IFNAR),adapter proteins(e.g.,MYD88),ubiquitin ligases(e.g.,A20),and transcription factors(e.g.,NF-κB,IRFs,and STATs)form complex signal transduction networks to control ACOD1 expression in a context-dependent manner.Functionally,ACOD1 mediates itaconate production,oxidative stress,and antigen processing and plays dual roles in immunity and diseases.On the one hand,activation of the ACOD1 pathway may limit pathogen infection and promote embryo implantation.On the other hand,abnormal ACOD1 expression can lead to tumor progression,neurodegenerative disease,and immune paralysis.Further understanding of the function and regulation of ACOD1 is important for the application of ACOD1-based therapeutic strategies in disease.

Systems-based approaches to study immunometabolism

Technical advances at the interface of biology and computation,such as single-cell RNA-sequencing(scRNA-seq),reveal new layers of complexity in cellular systems.An emerging area of investigation using the systems biology approach is the study of the metabolism of immune cells.The diverse spectra of immune cell phenotypes,sparsity of immune cell numbers in vivo,limitations in the number of metabolites identified,dynamic nature of cellular metabolism and metabolic fluxes,tissue specificity,and high dependence on the local milieu make investigations in immunometabolism challenging,especially at the single-cell level.In this review,we define the systemic nature of immunometabolism,summarize cell-and system-based approaches,and introduce mathematical modeling approaches for systems interrogation of metabolic changes in immune cells.We close the review by discussing the applications and shortcomings of metabolic modeling techniques.With systems-oriented studies of metabolism expected to become a mainstay of immunological research,an understanding of current approaches toward systems immunometabolism will help investigators make the best use of current resources and push the boundaries of the discipline.

Immunometabolism:a new dimension in immunotherapy resistance

Immune checkpoint inhibitors(ICIs)have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment,while substantial patients remain unresponsive or develop resistance to ICIs as a single agent,which is traceable to cellular metabolic dysfunction.Although dysregulated metabolism has long been adjudged as a hallmark of tumor,it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes.Correspondingly,people used to pay more attention to the effect of tumor cell metabolism on immunocytes,but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation,which opens up a whole new frontier called immunometabolism.The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy,whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response.Herein,we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes,and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.

Shedding new light on atherosclerosis therapeutics:Nanomedicines targeting atherosclerotic immune microenvironment

Atherosclerosis(AS)leads to atherosclerotic cardiovascular disease(ASCVD),the predominant cause of death worldwide.As traditional lipid-lowering therapies have encountered a bottleneck in dealing with diverse types of atherosclerotic plaques and ASCVD,alternative therapies that can target other mechanisms are urgently needed.Recent studies have revealed that AS is rooted in disrupted immune responses,such as chronic local inflammation and autoimmune responses,and immunotherapies have emerged as a nascent avenue to control plaque development owing to their satisfactory effects and high cost efficiency.The atherosclerotic immune microenvironment(AIME)is the microenvironment in which diverse immune responses occur dynamically.AIME is characterized by persistent inflammatory responses,shifted immunometabolism,and the formation of adventitial neuroimmune cardiovascular interfaces,all of which are regarded as prospective targets for AS immunotherapy.Recently,the advent of nanotechnology has advanced AS immunotherapy targeting the AIME.Manifold nanoplatforms have greatly enriched AS therapeutics owing to their multimodal imaging and multichannel intervention capabilities.Here,we offer an overview of AIME and discuss how nanomedicines can assist in AS diagnosis and intervention.We introduce nanoplatforms integrated with imaging techniques,such as magnetic resonance imaging,photoacoustic imaging,fluorescence imaging,positron emission tomography,and ultrasound imaging,which can target AIME to realize plaque diagnosis.Moreover,we elaborated on nanomaterials that regulate innate immune responses,adaptive immune responses,and aberrant immunometabolism to achieve AIME modulation.Furthermore,we highlight the possible future directions of AS therapeutics,with a focus on AIME-targeted nanomedicines.

Role of nutraceuticals during the transition period of dairy cows: a review

The transition period of dairy cattle is characterized by a number of metabolic, endocrine, physiologic, and immune adaptations, including the occurrence of negative energy balance, hypocalcemia, liver dysfunction, overt systemic inflammatory response, and oxidative stress status. The degree and length of time during which these systems remain out of balance could render cows more susceptible to disease, poor reproductive outcomes, and less efficient for milk production and quality. Studies on both monogastrics and ruminants have reported the health benefits of nutraceuticals(e.g. probiotics, prebiotics, dietary lipids, functional peptides, phytoextracts) beyond nutritional value, interacting at different levels of the animal's physiology. From a physiological standpoint, it seems unrealistic to disregard any systemic inflammatory processes. However, an alternate approach is to modulate the inflammatory process per se and to resolve the systemic response as quickly as possible.To this aim, a growing body of literature underscores the efficacy of nutraceuticals(active compounds) during the critical phase of the transition period. Supplementation of essential fatty acids throughout a 2-month period(i.e. a month before and a month after calving) successfully attenuates the inflammatory status with a quicker resolution of phenomenon. In this context, the inflammatory and immune response scenario has been recognized to be targeted by the beneficial effect of methyl donors, such as methionine and choline, directly and indirectly modulating such response with the increase of antioxidants GSH and taurine. Indirectly by the establishment of a healthy gastrointestinal tract, yeast and yeast-based products showed to modulate the immune response, mitigating negative effects associated with parturition stress and consequent disorders.The use of phytoproducts has garnered high interest because of their wide range of actions on multiple tissue targets encompassing a series of antimicrobial, antiviral, antioxidant, immune-stimulating, rumen fermentation, and microbial modulation effects. In this review, we provide perspectives on investigations of regulating the immune responses and metabolism using several nutraceuticals in the periparturient cow.

Metabolic regulation of immune responses to cancer

The tumor microenvironment is an ecosystem composed of multiple types of cells, such as tumor cells, immune cells, and cancerassociated fibroblasts. Cancer cells grow faster than non-cancerous cells and consume larger amounts of nutrients. The rapid growth characteristic of cancer cells fundamentally alters nutrient availability in the tumor microenvironment and results in reprogramming of immune cell metabolic pathways. Accumulating evidence suggests that cellular metabolism of nutrients, such as lipids and amino acids, beyond being essential to meet the bioenergetic and biosynthetic demands of immune cells, also regulates a broad spectrum of cellular signal transduction, and influences immune cell survival, differentiation, and anti-tumor effector function. The cancer immunometabolism research field is rapidly evolving, and exciting new discoveries are reported in high-profile journals nearly weekly. Therefore, all new findings in this field cannot be summarized within this short review. Instead, this review is intended to provide a brief introduction to this rapidly developing research field, with a focus on the metabolism of two classes of important nutrients-lipids and amino acids-in immune cells. We highlight recent research on the roles of lipids and amino acids in regulating the metabolic fitness and immunological functions of T cells, macrophages, and natural killer cells in the tumor microenvironment. Furthermore, we discuss the possibility of “editing” metabolic pathways in immune cells to act synergistically with currently available immunotherapies in enhancing anti-tumor immune responses.

Nanoparticle-Mediated Lipid Metabolic Reprogramming of T Cells in Tumor Microenvironments for Immunometabolic Therapy

We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming.Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles(F/ANs),and the surfaces of F/ANs were modified with an anti-CD3e f(ab′)2 fragment,yielding aCD3/F/ANs.An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/ANs.aCD3/F/AN-treated T cells exhibited clear mitochondrial cristae,a higher membrane potential,and a greater mitochondrial oxygen consumption rate under glucose-deficient conditions compared with T cells treated with other nanoparticle preparations.Peroxisome proliferatoractivated receptor-αand downstream fatty acid metabolismrelated genes are expressed to a greater extent in aCD3/F/AN-treated T cells.Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment.Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells.In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues.The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor growth.Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.

Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis

A novel rheumatoid arthritis(RA)synovial fluid protein,Syntenin-1,and its receptor,Syndecan-1(SDC-1),are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes(FLS).Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9,IL-1β,IL-6,and CCL2 through SDC-1 ligation and HIF1α,or mTOR activation.Mechanistically,Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling.In Syntenin-1 reprogrammed endothelial cells,the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors,AMPK,PGC-1α,citrate,and inactive oxidative phosphorylation.Conversely,RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity.The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression.We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS,which are also represented in RA explants.Similar to RA explants,morphological and transcriptome studies authenticated the importance of VEGFR1/2,Notch1,RAPTOR,and HIF1αpathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals.Consistently,dysregulation of SDC-1,mTOR,and HIF1αnegated Syntenin-1 inflammatory phenotype in RA explants,while inhibition of HIF1αimpaired synovial angiogenic imprint amplified by Syntenin-1.In conclusion,since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood,targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.

The immunology of sickness metabolism

Everyone knows that an infection can make you feel sick.Although we perceive infection-induced changes in metabolism as a pathology,they are a part of a carefully regulated process that depends on tissue-specific interactions between the immune system and organs involved in the regulation of systemic homeostasis.Immune-mediated changes in homeostatic parameters lead to altered production and uptake of nutrients in circulation,which modifies the metabolic rate of key organs.This is what we experience as being sick.The purpose of sickness metabolism is to generate a metabolic environment in which the body is optimally able to fight infection while denying vital nutrients for the replication of pathogens.Sickness metabolism depends on tissue-specific immune cells,which mediate responses tailored to the nature and magnitude of the threat.As an infection increases in severity,so do the number and type of immune cells involved and the level to which organs are affected,which dictates the degree to which we feel sick.Interestingly,many alterations associated with metabolic disease appear to overlap with immune-mediated changes observed following infection.Targeting processes involving tissue-specific interactions between activated immune cells and metabolic organs therefore holds great potential for treating both people with severe infection and those with metabolic disease.In this review,we will discuss how the immune system communicates in situ with organs involved in the regulation of homeostasis and how this communication is impacted by infection.

Cellular metabolism regulates the differentiation and function of T-cell subsets

Tcells are an important component of adaptive immunity and protect the host from infectious diseases and cancers.However,uncontrolled T cell immunity may cause autoimmune disorders.In both situations,antigen-specific T cells undergo clonal expansion upon the engagement and activation of antigens.Cellular metabolism is reprogrammed to meet the increase in bioenergetic and biosynthetic demands associated with effector T cell expansion.Metabolites not only serve as building blocks or energy sources to fuel cell growth and expansion but also regulate a broad spectrum of cellular signals that instruct the differentiation of multiple T cell subsets.The realm of immunometabolism research is undergoing swift advancements.Encapsulating all the recent progress within this concise review in not possible.Instead,our objective is to provide a succinct introduction to this swiftly progressing research,concentrating on the metabolic intricacies of three pivotal nutrient classes—lipids,glucose,and amino acids—in T cells.We shed light on recent investigations elucidating the roles of these three groups of metabolites in mediating the metabolic and immune functions of T cells.Moreover,we delve into the prospect of“editing”metabolic pathways within T cells using pharmacological or genetic approaches,with the aim of synergizing this approach with existing immunotherapies and enhancing the efficacy of antitumor and antiinfection immune responses.

The influence of metabolic disorders on adaptive immunity

The immune system plays a crucial role in protecting the body from invading pathogens and maintaining tissue homoeostasis.Maintaining homoeostatic lipid metabolism is an important aspect of efficient immune cell function and when disrupted immune cell function is impaired.There are numerous metabolic diseases whereby systemic lipid metabolism and cellular function is impaired.In the context of metabolic disorders,chronic inflammation is suggested to be a major contributor to disease progression.A major contributor to tissue dysfunction in metabolic disease is ectopic lipid deposition,which is generally caused by diet and genetic factors.Thus,we propose the idea,that similar to tissue and organ damage in metabolic disorders,excessive accumulation of lipid in immune cells promotes a dysfunctional immune system(beyond the classical foam cell)and contributes to disease pathology.Herein,we review the evidence that lipid accumulation through diet can modulate the production and function of immune cells by altering cellular lipid content.This can impact immune cell signalling,activation,migration,and death,ultimately affecting key aspects of the immune system such as neutralising pathogens,antigen presentation,effector cell activation and resolving inflammation.

CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKM supports antitumor immunity

Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

Metabolic Dysregulation and Metabolite Imbalances in Acuteon-chronic Liver Failure:Impact on Immune Status

Liver failure encompasses a range of severe clinical syndromes resulting from the deterioration of liver function,triggered by factors both within and outside the liver.While the definition of acute-on-chronic liver failure(ACLF)may vary by region,it is universally recognized for its association with multiorgan failure,a robust inflammatory response,and high short-term mortality rates.Recent advances in metabolomics have provided insights into energy metabolism and metabolite alterations specific to ACLF.Additionally,immunometabolism is increasingly acknowledged as a pivotal mechanism in regulating immune cell functions.Therefore,understanding the energy metabolism pathways involved in ACLF and investigating how metabolite imbalances affect immune cell functionality are crucial for developing effective treatment strategies for ACLF.This review methodically examined the immune and metabolic states of ACLF patients and elucidated how alterations in metabolites impact immune functions,offering novel perspectives for immune regulation and therapeutic management of liver failure.

Analysis of the Immune Response by Standardized Whole‑Blood Stimulation with Metabolism Modulation

The immune system defends the body from infection and plays a vital role in a wide range of health conditions.Metabolism afects a series of physiological processes,including those linked to the function of human immune system.Cellular metabolism modulates immune cell activation and cytokine production.Understanding the relationship between metabolism and immune response has important implications for the development of immune-based therapeutics.However,the deployment of large-scale functional assays to investigate the metabolic regulation of immune response has been limited by the lack of standardized procedures.Here,we present a protocol for the analysis of immune response using standardized whole-blood stimulation with metabolism modulation.Diverse immune stimuli including pattern recognition receptor(PRR)ligands and microbial stimuli were incubated with fresh human whole blood.The metabolic inhibitors were used to modulate metabolic status in the immune cells.The variable immune responses after metabolic interventions were evaluated.We described in detail the main steps involved in the whole-blood stimulation and cytokines quantifcation,namely,collection and treatment of whole blood,preparation of samples and controls,cytokines detection,and stimulation with metabolic interventions.The metabolic inhibitors for anabolic pathways and catabolic pathways exert selective efects on the production of cytokines from immune cells.In addition to a robust and accurate assessment of immune response in cohort studies,the standardized whole-blood stimulation with metabolic regulation might provide new insights for modulating immunity.

Circadian metabolism regulates the macrophage inflammatory response

Macrophages are an integral part of the innate immune system and coordinate host defense to microbial infections,as well as shaping the remodeling response after tissue injury.Metabolism is now appreciated to be a powerful and pervasive regulator of the identity and function of macrophages.Upon exposure to microbial ligands,macrophage inflammatory activation and the associated induction of phagocytosis,inflammatory responses,and other host defense activities are supported by dynamic changes to cellular metabolism.Of note,metabolic activity is robustly regulated in a circadian fashion,with many metabolic processes displaying peak activity in one phase of the circadian cycle and trough activity in an antiphase manner.Here,we review recent findings suggesting that circadian metabolism influences macrophage activities and particularly the inflammatory response.First,we summarize macrophage activities known to display time-of-day–dependent variation and their mechanistic basis.Second,we review metabolic processes that have been shown to be rhythmically regulated in macrophages and discuss how such circadian metabolism affects or is likely to affect macrophage activities.Third,we discuss the concept of entrainment of the macrophage clock,and consider how loss of rhythmic regulation of macrophage activities may contribute to pathophysiological conditions like shift work,obesity,and aging.Finally,we propose that circadian metabolism can be used to understand the rationale and mechanistic basis of dynamic regulation of inflammatory responses during infection.

Helper T cell differentiation

CD4^(+)T helper cells are key regulators of host health and disease.In the original model,specialized subsets of T helper cells are generated following activation through lineage-specifying cytokines and transcriptional programs,but recent studies have revealed increasing complexities for CD4^(+)T-cell differentiation.Here,we first discuss CD4^(+)T-cell differentiation from a historical perspective by highlighting the major studies that defined the distinct subsets of T helper cells.We next describe the mechanisms underlying CD4^(+)T-cell differentiation,including cytokine-induced signaling and transcriptional networks.We then review current and emerging topics of differentiation,including the plasticity and heterogeneity of T cells,the tissue-specific effects,and the influence of cellular metabolism on cell fate decisions.Importantly,recent advances in cutting-edge approaches,especially systems biology tools,have contributed to new concepts and mechanisms underlying T-cell differentiation and will likely continue to advance this important research area of adaptive immunity.