CD4+T细胞的新亚型：Th17细胞及其生物效应

辅助性T细胞通常分为Th1型和Th2型.20余年来,该分类方法形成了理解CD4 T细胞免疫生物学、固有免疫和适应性免疫调节理论的框架.近来研究发现,机体存在一种新型的不同于1型和2型的CD4 效应T细胞——辅助性17细胞(Thelp 17,Th 17),该细胞是由天然T细胞前体分化而来,具有独立的分化和发育调节机制,并特异性地产生白介素17(interleukin 17,IL-17)效应因子,在自身免疫性疾病和感染性疾病中发挥重要调节作用.这将对深入研究机体免疫调节、免疫病理和机体防御反应机制具有重要意义.就这种新型的辅助性T细胞的产生、发育分化机制和免疫调节效应研究进展做一简要综述.     

Th17 cell induction and immune regulatory effects

The T help 1 (Th1) and Th2 cell classification have provided the framework for understanding CD4⁺ T cell biology and the interplay between innate and adaptive immunity for almost two decades. Recent studies have defined a previously unknown arm of the CD4⁺ T cell effector response, the Th17 lineage, which promises to change our understanding of immune regulation, immune pathogenesis and host defense. The factors that specify differentiation of IL‐17 producing effector T cells from naïve T cell precursors are being rapidly discovered and are providing insights into mechanisms by which signals from cells of the innate immune system guide alternative pathways of Th1, Th2, or Th17 development. In this review, we will focus on recent studies that have identified new subsets of Th cells, new insights regarding the induced generation and differentiation mechanisms of Th17 cells and immune regulatory effects. J. Cell. Physiol. 211: 273–278, 2007. © 2007 Wiley‐Liss, Inc.     

IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia

Emerging evidence supports the concept that T helper type 17 (T(H)17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the T(H)17 lineage, and both were crucial for maintaining local control of the Gram-negative pulmonary pathogen, Klebsiella pneumoniae. Although both cytokines regulated CXC chemokines and granulocyte colony-stimulating factor production in the lung, only IL-22 increased lung epithelial cell proliferation and increased transepithelial resistance to injury. These data support the concept that the T(H)17 cell lineage and its effector molecules have evolved to effect host defense against extracellular pathogens at mucosal sites.     

产白介素-17T细胞在肺部细菌感染中的研究进展

目前产白介素-17(IL-17)T细胞主要包括了产IL-17 CD4+T细胞即Th17细胞、产IL-17γδT细胞和产IL-17 CD8+T细胞等。随着对Th17这一系细胞功能研究的不断深入,发现它们能通过产生IL-17和IL-22等细胞因子参与炎症反应。该文将对产IL-17 T细胞在肺部细菌感染中所起作用的最近研究进展进行综述。     

Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity

STAT3 activation has been observed in several autoimmune diseases, suggesting that STAT3-mediated pathways promote pathologic immune responses. We provide in vivo evidence that the fundamental role of STAT3 signaling in autoimmunity relates to its absolute requirement for generating T(H)17 T cell responses. We show that STAT3 is a master regulator of this pathogenic T cell subtype, acting at multiple levels in vivo, including T(H)17 T cell differentiation and cytokine production, as well as induction of RORgamma t and the IL-23R. Neither naturally occurring T(H)17 cells nor T(H)17-dependent autoimmunity occurs when STAT3 is ablated in CD4 cells. Furthermore, ablation of STAT3 signaling in CD4 cells results in increased T(H)1 responses, indicating that STAT3 signaling skews T(H) responses away from the T(H)1 pathway and toward the T(H)17 pathway. Thus, STAT3 is a candidate target for T(H)17-dependent autoimmune disease immunotherapy that could selectively inhibit pathogenic immune pathways.     

Human T cells that are able to produce IL-17 express the chemokine receptor CCR6

Some pathways of T cell differentiation are associated with characteristic patterns of chemokine receptor expression. A new lineage of effector/memory CD4+ T cells has been identified whose signature products are IL-17 cytokines and whose differentiation requires the nuclear receptor, RORgammat. These Th17 cells are critical effectors in mouse models of autoimmune disease. We have analyzed the association between chemokine receptor expression and IL-17 production for human T cells. Activating cord blood (naive) CD4+ T cells under conditions driving Th17 differentiation led to preferential induction of CCR6, CCR9, and CXCR6. Despite these data, we found no strong correlation between the production of IL-17 and expression of CCR9 or CXCR6. By contrast, our analyses revealed that virtually all IL-17-producing CD4+ T cells, either made in our in vitro cultures or found in peripheral blood, expressed CCR6, a receptor found on approximately 50% of CD4+ memory PBL. Compared with CD4+CD45RO+CCR6- cells, CD4+CD45RO+CCR6+ cells contained at least 100-fold more IL-17A mRNA and secreted 100-fold more IL-17 protein. The CCR6+ cells showed a similar enrichment in mRNA for RORgammat. CCR6 was likewise expressed on all IL-17-producing CD8+ PBL. CCR6 has been associated with the trafficking of T, B, and dendritic cells to epithelial sites, but has not been linked to a specific T cell phenotype. Our data reveal a fundamental feature of IL-17-producing human T cells and a novel role for CCR6, suggesting both new directions for investigating IL-17-related immune responses and possible targets for preventing inflammatory injury.     

Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells

Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by a wide range of clinical signs. The location of lesions in the CNS is variable and is a crucial determinant of clinical outcome. Multiple sclerosis is believed to be mediated by myelin-specific T cells, but the mechanisms that determine where T cells initiate inflammation are unknown. Differences in lesion distribution have been linked to the HLA complex, suggesting that T cell specificity influences sites of inflammation. We demonstrate that T cells that are specific for different myelin epitopes generate populations characterized by different T helper type 17 (T(H)17) to T helper type 1 (T(H)1) ratios depending on the functional avidity of interactions between TCR and peptide-MHC complexes. Notably, the T(H)17:T(H)1 ratio of infiltrating T cells determines where inflammation occurs in the CNS. Myelin-specific T cells infiltrate the meninges throughout the CNS, regardless of the T(H)17:T(H)1 ratio. However, T cell infiltration and inflammation in the brain parenchyma occurs only when T(H)17 cells outnumber T(H)1 cells and trigger a disproportionate increase in interleukin-17 expression in the brain. In contrast, T cells showing a wide range of T(H)17:T(H)1 ratios induce spinal cord parenchymal inflammation. These findings reveal critical differences in the regulation of inflammation in the brain and spinal cord.     

Act1 modulates autoimmunity through its dual functions in CD40L/BAFF and IL-17 signaling

Coordinated regulation of T and B cell-mediated immune responses plays a critical role in the control and modulation of autoimmune diseases. This review is focused on the adapter molecule Act1 and its regulation of autoimmunity through its impact on both T and B cell-mediated immune responses. Whereas Act1 molecule is an important negative regulator for B cell-mediated humoral immune responses through its function in CD40L and BAFF signaling, recent studies have shown that Act1 is also a key positive signaling component for IL-17 signaling pathway, critical for T(H)17-mediated autoimmune and inflammatory responses. The dual functions of Act1 are evident in Act1-deficient mice that displayed B cell-mediated autoimmune phenotypes (including dramatic increase in peripheral B cells, lymphadenopathy and splenomegaly, hypergammaglobulinemia and Sjogren's disease in association with Lupus Nephritis), but showed resistance to T(H)17-dependent EAE and colitis. Such seemingly opposite functions of Act1 in CD40-BAFFR and IL-17R signaling are orchestrated by different domains in Act1. Whereas Act1 interacts with the IL-17R through the C-terminal SEFIR domain, Act1 is recruited to CD40 and BAFFR indirectly, which is mediated by TRAF3 through the TRAF binding site in Act1. Such delicate regulatory mechanisms may provide a common vehicle to promote balance between host defense to pathogens and tolerance to self.     

Detection of Th1/Th2 cytokine signatures in yellow fever 17DD first-time vaccinees through ELISpot assay

Immunity to yellow fever (YF) is conferred by the interplay of humoral and cellular immune response. Despite the extensive literature on the humoral immune response to the YF vaccine virus, little is known about its cellular immune response to vaccination. The analysis of cytokine production by ex-vivo antigen-stimulated T cells has been considered as a valuable tool for understanding cellular immune response. Thus, we have analyzed two T(H)1/T(H)2 signature cytokines (IFN-gamma and IL-4) from 12 healthy first-time adults vaccinated with YF17DD virus. The cells, harvested on day 0 (before vaccination) and 7, 15 and 30 days after immunization were antigen-stimulated and analyzed by ELISpot. A significant increase in the number of spot-forming cells during the response to YF 17DD live virus stimulation by ELISpot assay was observed. IFN-gamma-and IL-4-producing cells were significantly increased on the 15th day after vaccination in all volunteers. These results presented herein are important for understanding the role of cytokines in the immune response to YF 17DD virus.