Aged regulatory T cells protect from autoimmune inflammation despite reduced STAT3 activation and decreased constraint of IL-17 producing T cells

Regulatory T cells (Tregs) are specialized CD4⁺ T lymphocytes helping defend against autoimmunity and inflammation. Although age is associated with increased inflammation and autoimmunity, few reports address age effects of immune regulation or auto‐aggressive T cells. We show here that young and aged naïve CD4⁺ T cells are equivalently auto‐aggressive in vivo in T cell‐driven autoimmune colitis. Young and aged CD4⁺ Tregs equally suppressed age‐matched T cell proliferation in vitro and controlled clinical and pathologic T cell‐driven autoimmune colitis, suggesting equivalent regulatory function. However, whereas young and aged CD4⁺ Tregs suppressed interferon (IFN)‐γ⁺ T cells equivalently in this model, aged CD4⁺ Tregs unexpectedly failed to restrain interleukin (IL)‐17⁺ T cells. Nonetheless, young and aged CD4⁺ Tregs equally restrained IL‐17⁺ T cells in vivo during acute inflammation, suggesting a chronic inflammation‐related defect in aged CD4⁺ Tregs. In support, aged Tregs expressed reduced STAT3 activation, a defect associated with poor IL‐17‐producing T cell restraint. Aged naïve mice had markedly increased programmed death (PD)‐1⁺ T cells, but these exhibited no significant auto‐aggressive or regulatory functions in T cell‐driven colitis. Young CD8⁺ CD122^? T cells induce autoimmune bone marrow failure, but we show that aged CD8⁺ CD122^? T cells do not. These data demonstrate no apparent age‐related increase in auto‐aggressive T cell behavior, but disclose previously unrecognized functional defects in aged CD4⁺ Tregs during chronic inflammation. IL‐17 can be inflammatory and contributes to certain autoimmune disorders. Reduced aged Treg function during chronic inflammation and reduced IL‐17 restraint could contribute to age‐related inflammation or autoimmunity.     

Thymus‐derived regulatory T cells restrain pro‐inflammatory Th1 responses by downregulating CD70 on dendritic cells

The severity and intensity of autoimmune disease in immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) patients and in scurfy mice emphasize the critical role played by thymus‐derived regulatory T cells (tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and excessive inflammatory responses, their suppressive mechanism remains elusive. Here, we demonstrate that tTregs selectively inhibit CD27/CD70‐dependent Th1 priming, while leaving the IL‐12‐dependent pathway unaffected. Immunized mice depleted of tTregs showed an increased response of IFN‐γ‐secreting CD4⁺ T cells that was strictly reliant on a functional CD27/CD70 pathway. In vitro studies revealed that tTregs downregulate CD70 from the plasma membrane of dendritic cells (DCs) in a CD27‐dependent manner. CD70 downregulation required contact between Tregs and DCs and resulted in endocytosis of CD27 and CD70 into the DC. These findings reveal a novel mechanism by which tTregs can maintain tolerance or prevent excessive, proinflammatory Th1 responses.     

Topical astilbin ameliorates imiquimod‐induced psoriasis‐like skin lesions in SKH‐1 mice via suppression dendritic cell‐Th17 inflammation axis

Astilbin, an essential component of Rhizoma smilacis glabrae, exerts significant antioxidant and anti‐inflammatory effects against various autoimmune diseases. We have previously reported that astilbin decreases proliferation and improves differentiation of HaCaT keratinocytes in a psoriatic model. The present study was designed to evaluate the potential therapeutic effects of topical administration of astilbin on an imiquimod (IMQ)‐induced psoriasis‐like murine model and to reveal their underlying mechanisms. Topical administration of astilbin at a lower dose alleviated IMQ‐induced psoriasis‐like skin lesions by inducing the differentiation of epidermal keratinocytes in mice, and the therapeutic effect was even better than that of calcipotriol. Moreover, the inflammatory skin disorder was relieved by astilbin treatment characterized by a reduction in both IL‐17‐producing T cell accumulation and psoriasis‐specific cytokine expression in skin lesions. Furthermore, we found that astilbin inhibited R837‐induced maturation and activation of bone marrow‐derived dendritic cells and decreased the expression of pro‐inflammatory cytokines by downregulating myeloid differentiation factor 88. Our findings provide the convincing evidence that lower doses of astilbin might attenuate psoriasis by interfering with the abnormal activation and differentiation of keratinocytes and accumulation of IL‐17‐producing T cells in skin lesions. Our results strongly support the pre‐clinical application of astilbin for psoriasis treatment.     

哮喘患者外周血Treg和Th1/Th2的变化及其与哮喘病情的关系

目的：探讨哮喘患者外周血调节性T细胞（Treg）以及辅助性T细胞（Th1/Th2）的比例的变化,探讨其在哮喘的临床治疗中的作用。方法：80例哮喘患者（哮喘组）按临床表现分为急性发作期组（54例）和缓解期组（26例）,同时选择50例健康体检者。应用流式细胞仪检测上述各组外周血CD4＋CD25＋Foxp3＋Treg、CD4＋IFN-γ＋Th1和CD4＋IL-4＋Th2细胞水平,并进行统计学分析。结果：哮喘组CD4＋CD25＋Foxp3＋Treg水平亦明显低于正常对照组（P〈0.05。其中急性发作期组Treg水平明显低于缓解期组和正常对照组（P〈0.05）。而哮喘组Th1/Th2比值显著低于对照组（P〈0.05）,且在哮喘急性发作组中Th1/Th2比值显著低于缓解期组和正常对照组（P〈0.05）。结论：提示Treg和Th在哮喘的发生和发展中起着重要的作用。     

哮喘患者外周血Treg和Th1/Th2的变化及其与哮喘病情的关系

目的:探讨哮喘患者外周血调节性T细胞(Treg)以及辅助性T细胞(Th1/Th2)的比例的变化,探讨其在哮喘的临床治疗中的作用。方法:80例哮喘患者(哮喘组)按临床表现分为急性发作期组(54例)和缓解期组(26例),同时选择50例健康体检者。应用流式细胞仪检测上述各组外周血CD4+CD25+Foxp3+Treg、CD4+IFN-γ+Th1和CD4+IL-4+Th2细胞水平,并进行统计学分析。结果:哮喘组CD4+CD25+Foxp3+Treg水平亦明显低于正常对照组(P<0.05。其中急性发作期组Treg水平明显低于缓解期组和正常对照组(P<0.05)。而哮喘组Th1/Th2比值显著低于对照组(P<0.05),且在哮喘急性发作组中Th1/Th2比值显著低于缓解期组和正常对照组(P<0.05)。结论:提示Treg和Th在哮喘的发生和发展中起着重要的作用。     

血红素加氧酶-1、树突状细胞和调节性T细胞在慢性气道炎症中的作用及相互关系

慢性气道炎症是多种肺部疾病的共同病理生理过程,是由多种炎症细胞、炎症介质及细胞因子相互作用所致的气道病变。血红素加氧酶(HO)-1、树突状细胞(DC)和调节性T细胞(Treg)参与了气道炎症并发挥不同的作用,表现在HO-1具有抗炎抗氧化及保护细胞的作用;DC除可导致或持续气道炎症反应外,也具有负向调控作用,可诱导免疫耐受而抑制炎症的发展;而Treg可发挥免疫调抑功能,以此维持免疫稳态及抑制气道炎症。HO-1、DC和Treg相互作用,影响着气道炎症的发生发展。现对三者在气道炎症中的作用及相互关系进行综述。     

Multifunctional roles of the autoimmune disease-associated tyrosine phosphatase PTPN22 in regulating T cell homeostasis

The non-receptor tyrosine phosphatase PTPN22 has a vital function in inhibiting antigen-receptor signaling in T cells, while polymorphisms in the PTPN22 gene are important risk alleles in human autoimmune diseases. We recently reported that a key physiological function of PTPN22 was to prevent naïve T cell activation and effector cell responses in response to low affinity antigens. PTPN22 also has a more general role in limiting T cell receptor-induced proliferation. Here we present new data emphasizing this dual function for PTPN22 in T cells. Furthermore, we show that T cell activation modulates the expression of PTPN22 and additional inhibitory phosphatases. We discuss the implication of these findings for our understanding of the roles of PTPN22 in regulating T cell responses and in autoimmunity.     

Accumulation of pTreg cells is detrimental in late‐onset (aged) mouse model of multiple sclerosis

Although typically associated with onset in young adults, multiple sclerosis (MS) also attacks the elderly, which is termed late‐onset MS. The disease can be recapitulated and studied in a mouse model, experimental autoimmune encephalomyelitis (EAE). The onset of induced EAE is delayed in aged mice, but disease severity is increased relative to young EAE mice. Given that CD4⁺FoxP3⁺ regulatory T (Treg) cells play an ameliorative role in MS/EAE severity, and the aged immune system accumulates peripheral Treg (pTreg) cells, failure of these cells to prevent or ameliorate EAE disease is enigmatic. When analyzing the distribution of Treg cells in EAE mice, the aged mice exhibited a higher proportion of polyclonal (pan‐) pTreg cells and a lower proportion of antigen‐specific pTreg cells in the periphery but lower proportions of both pan‐ and antigen‐specific Treg cells in the central nervous system (CNS). Furthermore, in the aged inflamed CNS, CNS‐Treg cells exhibited a higher plasticity, and T effector (CNS‐Teff) cells exhibited greater clonal expansion, disrupting the Treg/Teff balance. Transiently inhibiting FoxP3 or depleting pTreg cells partially corrected Treg distribution and restored the Treg/Teff balance in the aged inflamed CNS, thereby ameliorating the disease in the aged EAE mice. These results provide evidence and mechanism that accumulated aged pTreg cells play a detrimental role in neuronal inflammation of aged MS.     

免疫细胞与炎症介质在肠炎发病中的作用

肠炎的起因是多样的,但引起粘膜的损伤而出现各种临床症状的机制却是相似的。近年来免疫生物学,分子免疫学的发展对肠道粘膜免疫功能的了解有了巨大的进步。肠炎的起因是病原或过敏原刺激活化了先天免疫和特异免疫系统的细胞,由肠道上皮细胞、巨噬细胞和淋巴细胞分泌多种细胞因子,这些细胞因子再活化或动员更多的细胞,并进一步分泌更多的因子,形成病原、细胞和因子之间的级联反应。由细胞与因子的综合作用,造成肠道局部的炎症。炎症因子和抗炎因子比例的消长决定了炎症的转归和预后。对炎症因子及其拮抗剂作用机制的了解,将有助于肠炎的诊断和治疗。     

Emerging role of bystander T cell activation in autoimmune diseases

Autoimmune disease is known to be caused by unregulated self-antigen-specific T cells, causing tissue damage. Although antigen specificity is an important mechanism of the adaptive immune system, antigen non-related T cells have been found in the inflamed tissues in various conditions. Bystander T cell activation refers to the activation of T cells without antigen recognition. During an immune response to a pathogen, bystander activation of self-reactive T cells via inflammatory mediators such as cytokines can trigger autoimmune diseases. Other antigen-specific T cells can also be bystander-activated to induce innate immune response resulting in autoimmune disease pathogenesis along with self-antigen-specific T cells. In this review, we summarize previous studies investigating bystander activation of various T cell types (NKT, γδ T cells, MAIT cells, conventional CD4⁺, and CD8⁺ T cells) and discuss the role of innate-like T cell response in autoimmune diseases. In addition, we also review previous findings of bystander T cell function in infection and cancer. A better understanding of bystander-activated T cells versus antigen-stimulated T cells provides a novel insight to control autoimmune disease pathogenesis.     

Emerging mechanisms of immune regulation: the extended B7 family and regulatory T cells

Whereas B7-1/B7-2 and CD28/cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) serve as the main switches regulating the clonal composition of activated naive T cells, other B7 family members fine-tune the expansion and properties of activated T cells. Inducible costimulatory molecule (ICOS)-B7h promotes T-dependent antibody isotype switching and expansion of effector cells. Effector T cells trafficking into inflamed tissues interact with antigen-presenting cells there and are regulated by PD-1 and its ligands. B7-H3 and B7x could control the interaction between effector T cells and the peripheral tissues. The different varieties of regulatory T cells could regulate both naive T cell activation and effector function through costimulatory receptor/ligands.     

Exosomes derived from pro‐inflammatory bone marrow‐derived mesenchymal stem cells reduce inflammation and myocardial injury via mediating macrophage polarization

Exosomes are served as substitutes for stem cell therapy, playing important roles in mediating heart repair during myocardial infarction injury. Evidence have indicated that lipopolysaccharide (LPS) pre‐conditioning bone marrow‐derived mesenchymal stem cells (BMSCs) and their secreted exosomes promote macrophage polarization and tissue repair in several inflammation diseases; however, it has not been fully elucidated in myocardial infarction (MI). This study aimed to investigate whether LPS‐primed BMSC‐derived exosomes could mediate inflammation and myocardial injury via macrophage polarization after MI. Here, we found that exosomes derived from BMSCs, in both Exo and L‐Exo groups, increased M2 macrophage polarization and decreased M1 macrophage polarization under LPS stimulation, which strongly depressed LPS‐dependent NF‐κB signalling pathway and partly activated the AKT1/AKT2 signalling pathway. Compared with Exo, L‐Exo had superior therapeutic effects on polarizing M2 macrophage in vitro and attenuated the post‐infarction inflammation and cardiomyocyte apoptosis by mediating macrophage polarization in mice MI model. Consequently, we have confidence in the perspective that low concentration of LPS pre‐conditioning BMSC‐derived exosomes may develop into a promising cell‐free treatment strategy for clinical treatment of MI.     

Isolation and characteristics of autoreactive T cells specific to aggrecan G1 domain from rheumatoid arthritis patients

NTRODUCTIONRheumatoid arthritis (RA) is a common disease characterized by the chroniclesion of polyarthritis. The etiology and pathogenesis of RA remain unknown. Autoimmunity to cartilage alltigens may play a significant role in the pathogenesis ofchronic inflammatory polyarthritis. It is commonly accepted that cell mediated immune responses are involved in chronic inflammation since T and B lymphocytes andatigen presenting cells were observed to be enriched in the synovium fluid of RA…     

Vdelta1+ T cells are crucial for repertoire formation of gammadelta T cells in the lung

The pulmonary resident T lymphocytes (RPLs) expressing a nearly invariant T cell receptor γδ heterodimer (γδTCR) migrate from fetal thymus to the lung epithlium, followed by RPL subsets expressing diverse sets of γδTCRs after birth. However, it remains unclear whether the fetal type Vγ6/Vδ1⁺ RPLs are essential for γδ T cell repertoire formation in the lung epithelium. In this study, we found a marked decrease in the number of γδRPLs at 4 weeks of age in Vδ1^−/− mice and they predominantly expressed Vγ6 and Vδ4 genes. The skewed diversity towards the Vδ4-(Dδ1)-Dδ2-Jδ2 junctional region was observed only in γδ RPLs from 4-week-old Vδ1^−/− mice, compared with those from 8-week-old Vδ1^−/− mice and the both ages of wild-type mice. These results suggest that the invariant Vδ1⁺ T cells are crucial not only for optimal γδ T cell expansion but also for affecting the migration or microenvironment for other γδ T cells in the lung epithelium.