Adaptive immunity in the host-microbiota dialog

The intestinal tract represents the largest mucosal surface and is a major site of multifaceted interactions between the host mucosal immune system and components of the intestinal microbiota. Host immune responses to the commensal microbiota are tightly controlled and, meanwhile, the microbiota actively shapes intestinal immune responses to itself. Appreciation of these interactions during health and disease may direct therapeutic approaches to a broad range of autoimmune and inflammatory disorders in humans. In this review, we will discuss findings on how the intestinal immune system, especially adaptive immune cells, helps accommodate the large number of resident bacteria, and in turn how the microbiota shapes intestinal immune responses to achieve mutualism.     

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota

The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3⁺ regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders.     

Roles of intestinal microbiota in response to cancer immunotherapy

Cancer immunotherapy has been significantly effective on multiple cancers; however, there are still a distinct number of non-responding patients and various immune-related adverse events in responding patients. It is known that heterogeneity of intestinal microbiota may lead to different outcomes of therapy. Previous studies have reported that intestinal microbiota is probably attributed to influence the efficacy of cancer immunotherapy. Some intestinal bacteria could synergize with immune checkpoint blockade agents and optimize the immune response against multiple cancers. Therefore, understanding the roles of intestinal microbiota could help to improve the clinical efficacy of cancer immunotherapy. In this review, we first introduced the close relationships between intestinal microbiota and intestinal immune system. Then, we described the emerging evidences that intestinal microbiota responses to cancer immunotherapy. Finally, we briefly reviewed the technical development on intestinal microbiota research.     

Contributions of the intestinal microbiome in lung immunity

The intestine is a critical site of immune cell development that not only controls intestinal immunity but extra‐intestinal immunity as well. Recent findings have highlighted important roles for gut microbiota in shaping lung inflammation. Here, we discuss interactions between the microbiota and immune system including T cells, protective effects of microbiota on lung infections, the role of diet in shaping the composition of gut microbiota and susceptibility to asthma, epidemiologic evidence implicating antibiotic use and microbiota in asthma and clinical trials investigating probiotics as potential treatments for atopy and asthma. The systemic effects of gut microbiota are partially attributed to their generating metabolites including short chain fatty acids, which can suppress lung inflammation through the activation of G protein‐coupled receptors. Thus, studying the interactions between microbiota and immune cells can lead to the identification of therapeutic targets for chronic lower respiratory diseases.     

Mucosal innate immune cells regulate both gut homeostasis and intestinal inflammation

Continuous exposure of intestinal mucosal surfaces to diverse microorganisms and their metabolites reflects the biological necessity for a multifaceted, integrated epithelial and immune cell‐mediated regulatory system. The development and function of the host cells responsible for the barrier function of the intestinal surface (e.g., M cells, Paneth cells, goblet cells, and columnar epithelial cells) are strictly regulated through both positive and negative stimulation by the luminal microbiota. Stimulation by damage‐associated molecular patterns and commensal bacteria‐derived microbe‐associated molecular patterns provokes the assembly of inflammasomes, which are involved in maintaining the integrity of the intestinal epithelium. Mucosal immune cells located beneath the epithelium play critical roles in regulating both the mucosal barrier and the relative composition of the luminal microbiota. Innate lymphoid cells and mast cells, in particular, orchestrate the mucosal regulatory system to create a mutually beneficial environment for both the host and the microbiota. Disruption of mucosal homeostasis causes intestinal inflammation such as that seen in inflammatory bowel disease. Here, we review the recent research on the biological interplay among the luminal microbiota, epithelial cells, and mucosal innate immune cells in both healthy and pathological conditions.     

Imprinting of the immune system by the microbiota early in life

The ontogeny and maturation of the immune system is modulated by the microbiota. During fetal life, the mother's microbiota produces compounds that are transferred to the fetus and offspring, and enhance the generation of innate immune cells. After birth, the colonizing microbiota induces the development of intestinal lymphoid tissues and maturation of myeloid and lymphoid cells, and imprints the immune system with a reactivity level that persists long after weaning into adulthood. When the cross-talk between host and microbiota is perturbed early in life, a pathological imprinting may develop that is characterized by excessive immune reactivity in adulthood, which translates into increased susceptibility to inflammatory pathologies. In this review, we discuss the recent data that demonstrate the existence of a time window of opportunity early in life during which mice and human have to be exposed to microbiota in order to develop a balanced immune system. We also discuss the factors involved in imprinting, such as the microbiota, immune cells and stromal cells, as well as the nature of imprinting.     

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

The intestinal epithelium forms a barrier between the microbiota and the rest of the body. In addition, beyond acting as a physical barrier, the function of intestinal epithelial cells (IECs) in sensing and responding to microbial signals is increasingly appreciated and likely has numerous implications for the vast network of immune cells within and below the intestinal epithelium. IECs also respond to factors produced by immune cells, and these can regulate IEC barrier function, proliferation and differentiation, as well as influence the composition of the microbiota. The mechanisms involved in IEC–microbe–immune interactions, however, are not fully characterized. In this review, we explore the ability of IECs to direct intestinal homeostasis by orchestrating communication between intestinal microbes and mucosal innate and adaptive immune cells during physiological and inflammatory conditions. We focus primarily on the most recent findings and call attention to the numerous remaining unknowns regarding the complex crosstalk between IECs, the microbiota and intestinal immune cells.     

Manipulation of epithelial integrity and mucosal immunity by host and microbiota-derived metabolites

The human intestinal tract contains a large number of microbes, their metabolites, and potentially harmful food antigens. The intestinal epithelium separates the mucosa where immune cells are located from luminal microbes by expressing various factors that assemble into physical and chemical barriers. In addition to epithelial cells, immune cells are essential for enforcing mucosal barriers through production of inflammatory and anti-inflammatory mediators. Intestinal microbiota, represented by gut ecological communities of living microorganisms, influences maturation and homeostasis of host immune system and contributes to the maintenance of the epithelial integrity with small molecules derived from their metabolism, termed metabolites. In turn, immune cells receive signals from microbiota, and may play key role in maintenance of a healthy bacterial composition and reinforcement of epithelial barrier functions, leading to the establishment of a host-bacterial mutualism. Alterations in the microbiota community and metabolome profiles are observed in patients with various disorders including inflammatory bowel disease. In this review, we will discuss physiological functions of the microbiota and its metabolites in regulating host immune system and reinforcing epithelial barrier functions. Further understanding of these processes will aid in identification of novel therapeutic targets and subsequent development of therapeutic interventions in a range of chronic inflammatory diseases.     

Intestinal IgA synthesis: a primitive form of adaptive immunity that regulates microbial communities in the gut

Our intestine is colonized by an impressive community of bacteria, that has profound effects on the immune functions. The relationship between gut microbiota and the immune system is one of reciprocity: bacteria have important contribution in nutrient processing and education of the immune system and conversely, the immune system, particularly gut-associated lymphoid tissues (GALT) plays a key role in shaping the repertoire of gut microbiota. In this review we discuss new insights into the role of IgA in the maintenance of immune homeostasis and the reciprocal interactions between gut B cells and intestinal bacteria.     

Controlling the frontier: Regulatory T-cells and intestinal homeostasis

The intestine represents one of the most challenging sites for the immune system as immune cells must be able to mount an efficient response to invading pathogens while tolerating the large number and diverse array of resident commensal bacteria. Foxp3⁺ regulatory T-cells (Tregs) play a non-redundant role at maintaining this balance. At the same time Treg cell differentiation and function can be modulated by the intestinal microbiota. In this review, we will discuss effector mechanisms of Treg cells in the intestine and how these cells can be influenced by the intestinal microbiota.     

The impact of lung microbiota dysbiosis on inflammation

Host−microbiota interaction plays fundamental roles in the homeostasis of mucosal immunity. Dysbiosis of intestinal microbiota has been demonstrated to participate in various immune responses and many multifactorial diseases. Study of intestinal microbiota has moved beyond the consequences of dysbiosis to the causal microbiota associated with diseases. However, studies of pulmonary microbiota and its dysbiosis are still in their infancy. Improvement of culture-dependent and -independent techniques has facilitated our understanding of lung microbiota that not only exists in healthy lung tissue but also exerts great impact on immune responses under both physiological and pathological conditions. In this review, we summarize recent progresses of lung microbiota dysbiosis and its impact on the local immune system that determines the balance of tolerance and inflammation. We discuss the causal roles of pulmonary dysbiosis under disease settings, and propose that the interaction between lung microbiota and host is critical for establishing the immune homeostasis in lung.     

肠道菌群影响肠道细胞免疫的研究进展

肠道是机体抵抗外源病原体入侵的重要防线之一，肠道B淋巴细胞及T淋巴细胞作为肠道适应性免疫系统的主要组成部分，其发育和分化受肠道微环境的影响。近年来的研究表明，肠道菌群与肠道免疫系统发育密切相关。本文主要综述肠道菌群对肠道B淋巴细胞、肠道T淋巴细胞的分化及其细胞功能的影响，并对肠道菌影响该过程的部分机制作出阐明，为肠道菌群与肠道免疫的相互作用机制研究奠定基础。     

Intestinal FoxO signaling is required to survive oral infection in Drosophila

The intestinal immune system is tailored to fight pathogens effectively while tolerating the indigenous microbiota. Impairments of this homeostatic interaction may contribute to the etiology of various diseases including inflammatory bowel diseases. However, the molecular architecture underlying this complex regulatory interaction is not well understood. Here, we show that the fruit fly Drosophila melanogaster has a multilayered intestinal immune system that ensures strictly localized antimicrobial responses. Enterocytes, a major cell population of the intestine, produced antimicrobial peptides (AMPs) in a FoxO- but not NF-κB-dependent manner. Consequently, animals impaired in FoxO-mediated signaling had a significantly lowered resistance to intestinal infections; they were unable to increase the expression of AMP genes and males showed an increased bacterial load in response to an infection. Conventional innate immune signaling converging onto NF-κB activation was operative in only a few regions of the intestine, comprising the proventriculus, copper cells, and intestinal stem cells. Taken together, our results imply that danger-mediated as well as conventional innate immune signaling constitute modules that contribute to the fruit fly's intestinal immune system. We propose that this special architecture ensures localized and efficient antimicrobial responses against invasive pathogens while preserving the microbiota.     

Antibiotics, microbiota, and immune defense

The gastrointestinal tract microbiota contributes to the development and differentiation of the mammalian immune system. The composition of the microbiota affects immune responses and affects susceptibility to infection by intestinal pathogens and development of allergic and inflammatory bowel diseases. Antibiotic administration, while facilitating clearance of targeted infections, also perturbs commensal microbial communities and decreases host resistance to antibiotic-resistant microbes. Here, we review recent advances that begin to define the interactions between complex intestinal microbial populations and the mammalian immune system and how this relation is perturbed by antibiotic administration. We further discuss how antibiotic-induced disruption of the microbiota and immune homeostasis can lead to disease and we review strategies to restore immune defenses during antibiotic administration.     

The biology of intestinal immunoglobulin A responses

The gut mucosa is exposed to a large community of commensal bacteria that are required for the processing of nutrients and the education of the local immune system. Conversely, the gut immune system generates innate and adaptive responses that shape the composition of the local microbiota. One striking feature of intestinal adaptive immunity is its ability to generate massive amounts of noninflammatory immunoglobulin A (IgA) antibodies through multiple follicular and extrafollicular pathways that operate in the presence or absence of cognate T-B cell interactions. Here we discuss the role of intestinal IgA in host-commensal mutualism, immune protection, and tolerance and summarize recent advances on the role of innate immune cells in intestinal IgA production.     

Depletion of Foxp3+ regulatory T cells is accompanied by an increase in the relative abundance of Firmicutes in the murine gut microbiome

A reciprocal interaction exists between the gut microbiota and the immune system. Regulatory T (Treg) cells are important for controlling immune responses and for maintaining the intestinal homeostasis but their precise influence on the gut microbiota is unclear. We studied the effects of Treg cell depletion on inflammation of the intestinal mucosa and analysed the gut microbiota before and after depletion of Treg cells using the DEpletion of REGulatory T cells (DEREG) mouse model. DNA was extracted from stool samples of DEREG mice and wild-type littermates at different time-points before and after diphtheria toxin application to deplete Treg cells in DEREG mice. The V3/V4 region of the 16S rRNA gene was used for studying the gut microbiota with Illumina MiSeq paired ends sequencing. Multidimensional scaling separated the majority of gut microbiota samples from late time-points after Treg cell depletion in DEREG mice from samples of early time-points before Treg cell depletion in these mice and from gut microbiota samples of wild-type mice. Treg cell depletion in DEREG mice was accompanied by an increase in the relative abundance of the phylum Firmicutes and by intestinal inflammation in DEREG mice 20 days after Treg cell depletion, indicating that Treg cells influence the gut microbiota composition. In addition, the variables cage, breeding and experiment number were associated with differences in the gut microbiota composition and these variables should be respected in murine studies.     

B cells as a critical node in the microbiota–host immune system network

Mutualism with our intestinal microbiota is a prerequisite for healthy existence. This requires physical separation of the majority of the microbiota from the host (by secreted antimicrobials, mucus, and the intestinal epithelium) and active immune control of the low numbers of microbes that overcome these physical and chemical barriers, even in healthy individuals. In this review, we address how B-cell responses to members of the intestinal microbiota form a robust network with mucus, epithelial integrity, follicular helper T cells, innate immunity, and gut-associated lymphoid tissues to maintain host–microbiota mutualism.     

Microbiota in autoimmunity and tolerance

The composition of a host's intestinal microbiota directs the type of mucosal and systemic immune responses by affecting the proportion and number of functionally distinct T cell subsets. In particular, the microbiota composition affects the differentiation of intestinal Th17 cells and Foxp3(+) regulatory T cells, both of which play critical roles in maintaining mucosal barrier functions and in controlling immunological homeostasis. In this review, we discuss the recent advances in our understanding of how the intestinal microbiota affects T cell differentiation and host susceptibility to autoimmune disease.     

The intestinal neuro-immune axis: crosstalk between neurons,immune cells,and microbes

The gastrointestinal tract is densely innervated by a complex network of neurons that coordinate critical physiological functions. Here, we summarize recent studies investigating the crosstalk between gut-innervating neurons, resident immune cells, and epithelial cells at homeostasis and during infection, food allergy, and inflammatory bowel disease. We introduce the neuroanatomy of the gastrointestinal tract, detailing gut-extrinsic neuron populations from the spinal cord and brain stem, and neurons of the intrinsic enteric nervous system. We highlight the roles these neurons play in regulating the functions of innate immune cells, adaptive immune cells, and intestinal epithelial cells. We discuss the consequences of such signaling for mucosal immunity. Finally, we discuss how the intestinal microbiota is integrated into the neuro-immune axis by tuning neuronal and immune interactions. Understanding the molecular events governing the intestinal neuro-immune signaling axes will enhance our knowledge of physiology and may provide novel therapeutic targets to treat inflammatory diseases.