大肠癌肿瘤微环境中Th17细胞与调节性T细胞的作用及临床意义

大肠癌是全球最常见的恶性肿瘤之一,大肠癌的发生、发展与肠内慢性炎症(CRC)密切相关,而部分炎症细胞及其分泌的细胞因子在这一过程中扮演着重要角色,肿瘤浸润效应T细胞与多种类型肿瘤病人的预后密切相关,辅助性T细胞17(Th17)是新近发现的一类CD4+效应T细胞亚群,在炎症、自身免疫性疾病和肿瘤中发挥积极作用.调节性T细胞(Tregs)在功能上是T细胞的免疫抑制亚群,在自身免疫耐受和抗肿瘤免疫中起重要作用.Th17细胞和Treg细胞之间的动态平衡在保持免疫调控功能中至关重要.     

The plasticity of human Treg and Th17 cells and its role in autoimmunity

CD4⁺ T helper cells are a central element of the adaptive immune system. They protect the organism against a wide range of pathogens and are able to initiate and control many immune reactions in combination with other cells of the adaptive and the innate immune system. Starting from a naive cell, CD4⁺ T cells can differentiate into various effector cell populations with specialized function. This subset specific differentiation depends on numerous signals and the strength of stimulation. However, recent data have shown that differentiated CD4⁺ T cell subpopulations display a high grade of plasticity and that their initial differentiation is not an endpoint of T cell development. In particular, FoxP3⁺ regulatory T cells (Treg) and Th17 effector T cells demonstrate a high grade of plasticity, which allow a functional adaptation to various physiological situations during an immune response. However, the plasticity of Treg and Th17 cells might also be a critical factor for autoimmune disease. Here we discuss the recent developments in CD4⁺ T cell plasticity with a focus on Treg and Th17 cells and its role in human autoimmune disease, in particular multiple sclerosis (MS).     

IL‐6: Regulator of Treg/Th17 balance

IL‐6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL‐6 has a very important role in regulating the balance between IL‐17‐producing Th17 cells and regulatory T cells (Treg). The two T‐cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T‐cell responses. IL‐6 induces the development of Th17 cells from naïve T cells together with TGF‐β; in contrast, IL‐6 inhibits TGF‐β‐induced Treg differentiation. Dysregulation or overproduction of IL‐6 leads to autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), in which Th17 cells are considered to be the primary cause of pathology. Given the critical role of IL‐6 in altering the balance between Treg and Th17 cells, controlling IL‐6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases. Here, we review the role of IL‐6 in regulating Th17/Treg balance and describe the critical functions of IL‐6 and Th17 in immunity and immune‐pathology.     

Th17细胞与肝脏疾病的研究进展

机体免疫系统是抵抗外来病原体和各种损害的防御系统,根据CD4^＋T细胞的功能经典地分为辅助性T细胞（Th1、Th2）、细胞毒性T细胞以及调节性T细胞（Treg）3个亚群。Th1介导细胞免疫,Th2介导体液免疫,而Treg则在维护机体免疫平衡中发挥重要作用。然而随着对自身免疫性疾病的研究,发现一群不同于Th1、Th2、Treg的新型CD4^＋T细胞亚群——Th17细胞。已证实Th17细胞与清除胞外病原体、炎症、自身免疫性疾病和肿瘤的发生发展有密切联系。随着人们对肝炎、肝纤维化和肝癌等肝病认识不断加深,这种新型的Th17细胞在这些疾病中发生发展的作用机制也不断的被研究者所关注。     

Impact of gut microbiota on gut-distal autoimmunity: a focus on T cells

The immune system is essential for maintaining a delicate balance between eliminating pathogens and maintaining tolerance to self-tissues to avoid autoimmunity. An enormous and complex community of gut microbiota provides essential health benefits to the host, particularly by regulating immune homeostasis. Many of the metabolites derived from commensals can impact host health by directly regulating the immune system. Many autoimmune diseases arise from an imbalance between pathogenic effector T cells and regulatory T (Treg) cells. Recent interest has emerged in understanding how cross-talk between gut microbiota and the host immune system promotes autoimmune development by controlling the differentiation and plasticity of T helper and Treg cells. At the molecular level, our recent study, along with others, demonstrates that asymptomatic colonization by commensal bacteria in the gut is capable of triggering autoimmune disease by molecular mimicking self-antigen and skewing the expression of dual T-cell receptors on T cells. Dysbiosis, an imbalance of the gut microbiota, is involved in autoimmune development in both mice and humans. Although it is well known that dysbiosis can impact diseases occurring within the gut, growing literature suggests that dysbiosis also causes the development of gut-distal/non-gut autoimmunity. In this review, we discuss recent advances in understanding the potential molecular mechanisms whereby gut microbiota induces autoimmunity, and the evidence that the gut microbiota triggers gut-distal autoimmune diseases.     

Th17与自身免疫性疾病

当初始CD4+T细胞接受抗原刺激时,在不同的细胞因子环境中分化为不同的淋巴细胞亚群.Th17作为一种新的T细胞亚群是在TGF-β与IL-6存在时经由孤独核受体(ROB)-γt途径分化而来,而当环境中仅有TGF-β时却分化为CD4+CD25+Foxp3+调节性T细胞(Tr).与Th1一样,Th17被认为在自身免疫性疾病和炎症反应的发生和进展中都发挥重要的病理作用,相反,Tr则起着抗炎和免疫负性调节的作用.因此Th1及Th17倾向的免疫应答可能导致炎症反应与自身免疫性疾病的发生和进展,故在体内阻断其相关的细胞因子IL-17、IL-6等则可使Th1、Th17及Tr重新保持平衡而对自身免疫性疾病产生治疗作用.     

The deviated balance between regulatory T cell and Th17 in autoimmunity

Identifying the regulatory T cells (Tregs) and Th17 cells led to breaking the dichotomy of Th1/Th2 cells axis in immune responses involved in several autoimmune diseases. It is now well known that Tregs and Th17 cells are main orchestra leaders in pathogenesis symphony of autoimmunity. While Tregs are protective cells in autoimmune diseases, Th17 cells enhance the progression of autoimmune responses through induction of various pro-inflammatory reactions. It seems that the progression of autoimmunity may be associated with increase in Th17 and decrease in Treg levels, so that skewed balance between Tregs and Th17 toward Th17 is a phenomenon, which could be observed during progression of several autoimmune diseases. Although it is suggested that expansion and transfer of Tregs can be a new therapeutic target for autoimmune diseases, however, recent data about the phenotype conversion of Tregs into Th17 cells obligate us to more investigation on this approaching. Thus, identifying the new factors that induce stable phenotype in Tregs and prevent their phenotype conversion into Th17 cells as well as targeting the factor, which can modulate their balance, might be recommended as a new promising therapeutic method for autoimmune therapy. In this review, we try to clarify the factors, which can affect on this balance in various autoimmune diseases, as new targets in treatment of these diseases.     

Tim-1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells

We show that the T-cell immunoglobalin mucin, Tim-1, initially reported to be expressed on CD4(+) T cells, is constitutively expressed on dendritic cells (DCs) and that its expression further increases after DC maturation. Tim-1 signaling into DCs upregulates costimulatory molecule expression and proinflammatory cytokine production, thereby promoting effector T-cell responses, while inhibiting Foxp3(+) Treg responses. By contrast, Tim-1 signaling in T cells only regulates Th2 responses. Using a high-avidity/agonistic anti-Tim-1 antibody as a co-adjuvant enhances the immunogenic function of DCs, decreases the suppressive function of Tregs, and substantially increases proinflammatory Th17 responses in vivo. The treatment with high- but not low-avidity anti-Tim-1 not only worsens experimental autoimmune encephalomyelitis (EAE) in susceptible mice but also breaks tolerance and induces EAE in a genetically resistant strain of mice. These findings indicate that Tim-1 has an important role in regulating DC function and thus shifts the balance between effector and regulatory T cells towards an enhanced immune response. By understanding the mechanisms by which Tim-1 regulates DC and T-cell responses, we may clarify the potential utility of Tim-1 as a target of therapy against autoimmunity, cancer, and infectious diseases.     

Loss of the balance between CD4Foxp3 regulatory T cells and CD4IL17A Th17 cells in patients with type 1 diabetes

The presence of low-grade chronic inflammation is a known feature of long standing diabetes type 1. Recently, two T cell subsets, that may contribute to the disease progression are under investigation. These are Treg cells, which are specialized T cell subset, that controls the activity of autoreactive and inflammatory cells and Th17 cells which are involved in the pathogenesis of inflammatory and autoimmune diseases. The balance between Treg and Th17 controls inflammation and is responsible for the proper function of the immune system. An decrease of Tregs and/or increase of Th17 may induce local inflammation, which in turn may hasten the development of diabetic complications. In the present study, we have demonstrated that the Treg/Th17 balance was broken in patients with diabetes type 1 and might contribute to the progression of microvascular angiopathy.     

The therapeutic efficacy of human adipose tissue-derived mesenchymal stem cells on experimental autoimmune hearing loss in mice

Autoimmune inner ear disease is characterized by progressive, bilateral although asymmetric, sensorineural hearing loss. Patients with autoimmune inner ear disease had higher frequencies of interferon-γ-producing T cells than did control subjects tested. Human adipose-derived mesenchymal stem cells (hASCs) were recently found to suppress effector T cells and inflammatory responses and therefore have beneficial effects in various autoimmune diseases. The aim of this study was to examine the immunosuppressive activity of hASCs on autoreactive T cells from the experimental autoimmune hearing loss (EAHL) murine model. Female BALB/c mice underwent β-tubulin immunization to develop EAHL; mice with EAHL were given hASCs or PBS intraperitoneally once a week for 6 consecutive weeks. Auditory brainstem responses were examined over time. The T helper type 1 (Th1)/Th17-mediated autoreactive responses were examined by determining the proliferative response and cytokine profile of splenocytes stimulated with β-tubulin. The frequency of regulatory T (Treg) cells and their suppressive capacity on autoreactive T cells were also determined. Systemic infusion of hASCs significantly improved hearing function and protected hair cells in established EAHL. The hASCs decreased the proliferation of antigen-specific Th1/Th17 cells and induced the production of anti-inflammatory cytokine interleukin-10 in splenocytes. They also induced the generation of antigen-specific CD4(+) CD25(+) Foxp3(+) Treg cells with the capacity to suppress autoantigen-specific T-cell responses. The experiment demonstrated that hASCs are one of the important regulators of immune tolerance with the capacity to suppress effector T cells and to induce the generation of antigen-specific Treg cells.     

T regulatory cells and their counterparts: masters of immune regulation

The interaction of environmental and genetic factors with the immune system can lead to the development of allergic diseases. The essential step in this progress is the generation of allergen-specific CD4⁺ T-helper (Th) type 2 cells that mediate several effector functions. The influence of Th2 cytokines leads to the production of allergen-specific IgE antibodies by B cells, development and recruitment of eosinophils, mucus production and bronchial hyperreactivity, as well as tissue homing of other Th2 cells and eosinophils. Meanwhile, Th1 cells may contribute to chronicity and the effector phases. T cells termed T regulatory (Treg) cells, which have immunosuppressive functions and cytokine profiles distinct from that of either Th1 or Th2 cells, have been intensely investigated during the last 13 years. Treg cell response is characterized by an abolished allergen-specific T cell proliferation and the suppressed secretion of Th1 and Th2-type cytokines. Treg cells are able to inhibit the development of allergen-specific Th2 and Th1 cell responses and therefore play an important role in a healthy immune response to allergens. In addition, Treg cells potently suppress IgE production and directly or indirectly suppress the activity of effector cells of allergic inflammation, such as eosinophils, basophils and mast cells. Currently, Treg cells represent an exciting area of research, where understanding the mechanisms of peripheral tolerance to allergens may soon lead to more rational and safer approaches for the prevention and cure of allergic diseases.     

Th17细胞与Th1、Treg细胞关系的研究进展

CD4~+T细胞在不同细胞因子环境中可分化为Th1、Th2、Treg、Th17四种亚群,在一定条件下,各Th细胞亚群之间可以互相转化,从而使机体的免疫效应和免疫抑制处于精细而复杂的平衡状态。Th17细胞与自身免疫性疾病和肿瘤的发生发展关系密切,研究Th17细胞与Th1细胞、Treg细胞之间的相互关系,对于预防和治疗自身免疫性疾病和肿瘤等临床难题意义重大。     

Interplay Between Effector Th17 and Regulatory T Cells

Introduction  Over two decades ago, T helper cells were classified into its functional subsets. Soon after the classical observation of Mosmann et al., immunologists agreed to accept the Th1/Th2 paradigm of the T helper subsets. Each subset is not only characterized by its specific cytokines pattern and effector functions but also by their properties to counter regulate each other’s functions. This classification helped to understand the complex principles of T helper cell biology and allowed us to comprehend different immune reactions in context of Th1 and Th2 subsets. Discussion  Although Th1 subsets thought to be the crucial player for most of the organ-specific autoimmune diseases like multiple sclerosis and type-1 diabetes but the loss of Th1 dominant cytokine, IFN-γ did not prevent the development of autoimmunity which raised the possibility of involvement of other Th subsets, different from Th1 cells in the induction of autoimmunity. Conclusion  Recently, a new subset of Th cells that predominantly produce IL-17 and induce autoimmunity has been discovered, and it is believed that this subset may be the major cell type involved in orchestrating tissue inflammation and autoimmunity. Recent data propose that the differentiation factors of Th17 cells reveal a link with induction of Foxp3⁺ regulatory T cells. Here, we review the interplay between Th17 and Foxp3⁺ T-reg cells and Tr1 cells during autoimmune inflammatory reaction.     

Specialized CC-chemokine secretion by Th1 cells in destructive autoimmune myocarditis

T helper (Th) 1-mediated immune responses are associated with adverse outcomes in a number of models of autoimmune disease. Previous work has focused on the role that cytokines secreted by Th1 cells play in mediating pathologic tissue injury. To evaluate other mechanisms by which Th1 cells may be specialized to coordinate the complex effector cell interactions of a destructive immune response, CD4+ T cells specific for influenza hemagglutinin (HA) were differentiated into Th1 or Th2 subsets and transferred into transgenic mice expressing HA under control of the beta myosin heavy chain promoter, which drives heart specific expression of HA. CD4+ T cells polarized to a Th1 phenotype mediated a more destructive myocarditis than Th2 cells. Strikingly, the Th1-mediated inflammation was comprised primarily of CD8+ T cells and macrophages, suggesting a specialized recruitment function for Th1 cells. Further studies revealed that Th1 and Th2 subsets had polarized secretion of certain CC-chemokines, including MIP-1alpha and RANTES, which have selective recruitment properties on effector cells. Th1 cell secreted factors were up to 1000-fold more potent in inducing CD8+ T cell migration compared to Th2 cell secreted factors, and this advantage was partially mediated by their specialized MIP-1alpha secretion. These findings indicate that Th subsets have distinct patterns of CC-chemokine secretion and this specialization by Th1 cells mediates the recruitment of cytotoxic effector cells into destructive inflammatory responses.     

Relationship between Th1/Th2 cytokine patterns and the arthritogenic response in collagen-induced arthritis

It is hypothesized that the balance of cytokines produced by Th1/Th2 subsets of T helper cells plays an important role in the development of autoimmune diseases. Murine collagen-induced arthritis (CIA) is an example of an autoimmune disease in which immunization with cartilage-derived type II collagen induces, firstly, a T cell response to type II collagen and, secondly, the manifestation of a destructive inflammatory response in affected joints. We have investigated the role of Th1/Th2 responses in the development of CIA by monitoring levels of interferon (IFN)-γ (a Th1 cytokine) and interleukin (IL)-4 and IL-10 (Th2 cytokines), and IL-1β and tumor necrosis factor (TNF) (pro-inflammatory cytokines) produced by cultured draining lymph node cells (LNC) from collagen-immunized DBA/1 mice during the induction phase of arthritis and throughout the time of clinical manifestation and subsequent remission of the disease. Although a transient increase in IL-10 was detected 3 days after immunization, Th2 cytokine production was found to be almost completely suppressed 6 days after immunization. In contrast, IFN-γ was detected in LNC cultures as early as 6 days after immunization and the addition of type II collagen to the culture medium resulted in an approximately 10-fold increase in IFN-γ production, indicating that a predominantly Th1 response had become established by this time. IFN-γ production by LNC was found to be further increased at the time of clinical manifestation of arthritis and could be up-regulated by co-culture with type II collagen. IL-10 was not detected in LNC cultures at the onset of arthritis and IL-4, although present, was found to be markedly suppressed in LNC cultures containing type II collagen. These findings indicate that Th1 responses are predominant at the time of onset of arthritis and that the activation of collagen-specific Th1 cells may result in suppression of Th2 activity. IFN-γ production declined progressively during the progression and subsequent remission of arthritis whereas levels of IL-10 increased and low, though persistent, levels of IL-4 were detected throughout this period. High levels of IL-1β and TNF-α production were detected at the onset of the disease. The role of Th1 responses in the development of CIA was further emphasized by the observation that immunization of mice with type II collagen in incomplete Freund's adjuvant, which normally fails to induce arthritis, resulted in a predominantly Th2 cytokine profile.     

Leptin deficiency impairs maturation of dendritic cells and enhances induction of regulatory T and Th17 cells

Leptin is an adipose‐secreted hormone that plays an important role in both metabolism and immunity. Leptin has been shown to induce Th1‐cell polarization and inhibit Th2‐cell responses. Additionally, leptin induces Th17‐cell responses, inhibits regulatory T (Treg) cells and modulates autoimmune diseases. Here, we investigated whether leptin mediates its activity on T cells by influencing dendritic cells (DCs) to promote Th17 and Treg‐cell immune responses in mice. We observed that leptin deficiency (i) reduced the expression of DC maturation markers, (ii) decreased DC production of IL‐12, TNF‐α, and IL‐6, (iii) increased DC production of TGF‐β, and (iv) limited the capacity of DCs to induce syngeneic CD4⁺ T‐cell proliferation. As a consequence of this unique phenotype, DCs generated under leptin‐free conditions induced Treg or T_H17 cells more efficiently than DCs generated in the presence of leptin. These data indicate important roles for leptin in DC homeostasis and the initiation and maintenance of inflammatory and regulatory immune responses by DCs.     

Th9细胞与自身免疫性疾病

Th1、Th2、Th17和调节性T细胞（Treg）亚群是CD4＋T细胞亚群中的重要成员,其参与了人类及动物自身免疫性疾病的发病过程.既往认为,IL-9是由CD4＋Th2细胞分泌的细胞因子,是机体免疫应答中重要的调节因子.最近研究表明,机体内可能存在着一群新型的具有分泌IL-9和IL-10能力的CD4＋Th细胞亚群,称之为＂Th9＂细胞.该细胞亚群与自身免疫性疾病的相关性尚不清楚.