Generation and Regulation of CD8+ Regulatory T Cells

Research into the suppressive activity of CD4+FoxP3+ T regulatory cells (Treg) has defined a sublineage of CD4+ cells that contribute to self-tolerance and resistance to autoimmune disease. Much less attention has been given to the potential contribution of regulatory sublineages of CD8+ cells. Analysis of a small fraction of CD8+ cells that target autoreactive CD4+ cells through recognition of the MHC class Ib molecule Qa-1 in mouse and HLA-E in human has revitalized interest in CD8+ Treg. Here we summarize recent progress and future directions of research into the role of this CD8+ sublineage in resistance to autoimmune disease

3D forced vibration of a layered half-space coupled with surface rigid-base oscillators

This paper investigates the spatial steady-state responses of a system comprising a layered half-space coupled with surface oscillators to harmonic loading and the related factors through a semi–analytical framework. The proposed scheme utilizes the multiple scattering technique to reformulate the response field into associated parts described by Green's functions. The verified scheme, incorporating an averaging technique, accommodates structure properties regarding arbitrary spatial distribution and rigid base kinematic constraints. Focusing on the impacts of the presence of neighboring buildings, typical comparative investigations on a specialized layered half-space case reveal that how the geometrical and mechanical characteristics of the closely spaced structures influence the overall vibrational responses. Besides highlighting the effects of the relative location of the source and receivers on the involved Structure-Soil-Structure Interaction (SSSI), further case studies demonstrate the practical value of the proposed approach for addressing real-world engineering challenges such as the preliminary prediction and mitigation of vibrations in urban areas

Activated mouse CD4+Foxp3−CD4^+Foxp3^− T cells facilitate melanoma metastasis via Qa-1-dependent suppression of NK-cell cytotoxicity

The regulatory activities of mouse $CD^4+Foxp3^+$ T cells on various immune cells, including NK cells, have been well documented. Under some conditions, conventional $CD4^+Foxp3^−$ T cells in the periphery are able to acquire inhibitory function on other T cells, but their roles in controlling innate immune cells are poorly defined. As a potential cellular therapy for cancer, ex vivo activated $CD4^+Foxp3^−$ effector T cells are often infused back in vivo to suppress tumor growth and metastasis. Whether such activated T cells could affect NK-cell control of tumorigenesis is unclear. In the present study, we found that mitogen-activated $CD4^+Foxp3^−$ T cells exhibited potent suppressor function on NK-cell proliferation and cytotoxicity in vitro, and notably facilitated B16 melanoma metastasis in vivo. Suppression of NK cells by activated $CD4^+Foxp3^−$ T cells is cell-cell contact dependent and is mediated by Qa-1:NKG2A interaction, as administration of antibodies blocking either Qa-1 or NKG2A could completely reverse this suppression, and significantly inhibited otherwise facilitated melanoma metastasis. Moreover, activated $CD4^+Foxp3^−$ cells from Qa-1 knockout mice completely lost the suppressor activity on NK cells, and failed to facilitate melanoma metastasis when transferred in vivo. Taken together, our findings indicate that innate anti-tumor response is counter regulated by the activation of adaptive immunity, a phenomenon we term as “activation-induced inhibition”. Thus, the regulatory role of activated $CD4^+Foxp3^−$ T cells in NK-cell activity must be taken into consideration in the future design of cancer therapies

The transcriptional coactivator TAZ regulates reciprocal differentiation of T(h)17 cells and T(reg) cells

自身免疫性疾病是一类机体对自身抗原发生免疫反应而导致自身多器官、组织受累的慢性炎症性疾病。目前大量研究表明机体内促炎症的TH17细胞和抑制炎症Treg细胞在类群数量和活化状态的失衡是造成自身免疫疾病的主要致病因素。陈兰芬教授和周大旺教授团队的前期研究发现小鼠中Hippo信号通路中激酶Mst1/2缺失导致免疫缺陷，机体易受病原体感染并伴随着严重自身免疫疾病。该研究揭示了Hippo 信号通路转录共激活因子TAZ在决定CD4+初始T细胞分化为促进炎症的TH17效应细胞和抑制免疫反应的Treg调节性细胞过程中发挥着关键作用，拓展了当前对于Hippo信号通路的相关研究内容。 陈兰芬，博士，厦门大学生命科学学院教授。【Abstraact】An imbalance in the lineages of immunosuppressive regulatory T cells (Treg cells) and the inflammatory TH17 subset of helper T cells leads to the development of autoimmune and/or inflammatory disease. Here we found that TAZ, a coactivator of TEAD transcription factors of Hippo signaling, was expressed under T H17 cell–inducing conditions and was required for TH17 differentiation and TH17 cell–mediated inflammatory diseases. TAZ was a critical co-activator of the TH17-defining transcription factor RORγt. In addition, TAZ attenuated Treg cell development by decreasing acetylation of the Treg cell master regulator Foxp3 mediated by the histone acetyltransferase Tip60, which targeted Foxp3 for proteasomal degradation. In contrast, under T regcell–skewing conditions, TEAD1 expression and sequestration of TAZ from the transcription factors RORγt and Foxp3 promoted Treg cell differentiation. Furthermore, deficiency in TAZ or overexpression of TEAD1 induced Treg cell differentiation, whereas expression of a transgene encoding TAZ or activation of TAZ directed TH17 cell differentiation. Our results demonstrate a pivotal role for TAZ in regulating the differentiation of Treg cells and TH17 cells.J. Avruch for comments on the manuscript.Supported by the National Basic Research Program (973) of China (2015CB910502 to L.C.), the National Natural Science Foundation of China (81422018 to L.C.; 31625010 and U1505224 to D.Z.; U1405225 and 81372617 to L.C.; J1310027 to D.Z.; 81472229 to L.H.; and 31600698 to J. Geng), the 111 Projects (B12001 and B06016), China's 1000 Young Talents Program (D.Z., and L.C.), the Fundamental Research Funds for the Central Universities of China-Xiamen University (20720160071 to D.Z. and 20720160054 to L.H.) and Major disease research projects of Xiamen (3502Z20149029 to L.C.)

Priming of NLRP3 inflammasome activation 1 by Msn Kinase MINK1 in Macrophages

The nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome is essential in inflammation and inflammatory disorders. Phosphorylation at various sites on NLRP3 differentially regulates inflammasome activation. The Ser725 phosphorylation site on NLRP3 is depicted in multiple inflammasome activation scenarios, but the importance and regulation of this site has not been clarified. The present study revealed that the phosphorylation of Ser725 was an essential step for the priming of the NLRP3 inflammasome in macrophages. We also showed that Ser725 was directly phosphorylated by misshapen (Msn)/NIK-related kinase 1 (MINK1), depending on the direct interaction between MINK1 and the NLRP3 LRR domain. MINK1 deficiency reduced NLRP3 activation and suppressed inflammatory responses in mouse models of acute sepsis and peritonitis. Reactive oxygen species (ROS) upregulated the kinase activity of MINK1 and subsequently promoted inflammasome priming via NLRP3 Ser725 phosphorylation. Eliminating ROS suppressed NLRP3 activation and reduced sepsis and peritonitis symptoms in a MINK1-dependent manner. Altogether, our study reveals a direct regulation of the NLRP3 inflammasome by Msn family kinase MINK1 and suggests that modulation of MINK1 activity is a potential intervention strategy for inflammasome-related diseases

Qa-1b-Dependent Modulation of Dendritic Cell and NK Cell Cross-Talk In Vivo

Abstract Dendritic cells (DC) trigger activation and IFN-γ release by NK cells in lymphoid tissues, a process important for the polarization of Th1 responses. Little is known about the molecular signals that regulate DC-induced NK cell IFN-γ synthesis. In this study, we analyzed whether the interaction between Qa-1b expressed on DC and its CD94/NKG2A receptor on NK cells affects this process. Activation of DC using CpG-oligodeoxynucleotides in Qa-1b-deficient mice, or transfer of CpG-oligodeoxynucleotide-activated Qa-1b-deficient DC into wild-type mice, resulted in dramatically increased IFN-γ production by NK cells, as compared with that induced by Qa-1b-expressing DC. Masking the CD94/NKG2A inhibitory receptor on NK cells in wild-type mice similarly enhanced the IFN-γ response of these cells to Qa-1b-expressing DC. Furthermore, NK cells from CD94/NKG2A-deficient mice displayed higher IFN-γ production upon DC stimulation. These results demonstrate that Qa-1b is critically involved in regulating IFN-γ synthesis by NK cells in vivo through its interaction with CD94/NKG2A inhibitory receptors. This receptor-ligand interaction may be essential to prevent unabated cytokine production by NK cells during an inflammatory response.</jats:p

T Cell Costimulation through CD28 Depends on Induction of the Bcl-xγ Isoform: Analysis of Bcl-xγ–deficient Mice

The molecular basis of CD28-dependent costimulation of T cells is poorly understood. Bcl-xγ is a member of the Bcl-x family whose expression is restricted to activated T cells and requires CD28-dependent ligation for full expression. We report that Bcl-xγ–deficient (Bcl-xγ−/−) T cells display defective proliferative and cytokine responses to CD28-dependent costimulatory signals, impaired memory responses to proteolipid protein peptide (PLP), and do not develop PLP-induced experimental autoimmune encephalomyelitis (EAE). In contrast, enforced expression of Bcl-xγ largely replaces the requirement for B7-dependent ligation of CD28. These findings identify the Bcl-xγ cytosolic protein as an essential downstream link in the CD28-dependent signaling pathway that underlies T cell costimulation

Phosphatase PP2A is essential for T_H17 differentiation

Phosphatase PP2A expression levels are positively correlated to the clinical severity of systemic lupus erythematosus (SLE) and IL17A cytokine overproduction, indicating a potential role of PP2A in controlling TH17 differentiation and inflammation. By generating a mouse strain with ablation of the catalytic subunit α of PP2A in peripheral mature T cells (PP2A cKO), we demonstrate that the PP2A complex is essential for TH17 differentiation. These PP2A cKO mice had reduced TH17 cell numbers and less severe disease in an experimental autoimmune encephalomyelitis (EAE) model. PP2A deficiency also ablated C-terminal phosphorylation of SMAD2 but increased C-terminal phosphorylation of SMAD3. By regulating the activity of RORγt via binding, the changes in the phosphorylation status of these R-SMADs reduced Il17a gene transcription. Finally, PP2A inhibitors showed similar effects on TH17 cells as were observed in PP2A cKO mice, i.e., decreased TH17 differentiation and relative protection of mice from EAE. Taken together, these data demonstrate that phosphatase PP2A is essential for TH17 differentiation and that inhibition of PP2A could be a possible therapeutic approach to controlling TH17-driven autoimmune diseases.</p

Regulation of FcϵRI-mediated signaling and mast cell activation by adaptor protein Tespa1 (P1068)

Abstract Tespa1 (thymocyte-expressed, positive selection-associated 1) is a newly identified adaptor protein that is expressed in T cells, B cells and mast cells. Our previous study revealed its critical role in mediating TCR signaling and thymocyte positive selection. Tespa1-deficient mice have fewer mature CD4+ and CD8+ SP cells in thymus, reflecting the impairment of T cell development in these mice. We further revealed that Tespa1 interacts with Lat signolosome components Grb2 and PLC-γ1 and is essential for the assembly of this signolosome and mediating of downstream signals. Tespa1 is also highly expressed in Mast cells. Here we further explored the role of Tespa1 in Mast cell activation. We found that disruption of Tespa1 causes mast cells to be hyperresponsive upon the stimulation of FceRI receptor, evidenced by enhanced degranulation, cytokine production, and their ability to mediate anaphylaxis. We also found that more Grb2 and PLC-γ1 were recruited to the LAT1 signolosome rather than LAT2 signolosome, suggesting Tespa1 might regulate the balance of LAT1 and LAT2 signolosome assembly and downstream distal signaling transduction in mast cells.</jats:p