Search

Aloperine is an anti-inflammatory compound isolated from the Chinese herb Sophora alopecuroides L. Previously, our group has reported that the generation of induced Treg was promoted by aloperine treatment in a mouse colitis model. However, the effect of aloperine on effector T cell subsets remains unclear. We therefore carefully examined the effect of aloperine on the differentiation of major subsets of T helper cells. Based on our results, psoriasis, a Th17 dominant skin disease, is selected to explore the potential therapeutic effect of aloperine in vivo. Herein, we demonstrated that topical application of aloperine suppressed epidermal proliferation, erythema, and infiltration of inflammatory cells in skin lesions. Mechanistic studies revealed that aloperine suppressed the differentiation of Th17 cells directly through inhibiting the phosphorylation of STAT3 or indirectly through impairing the secretion of Th17-promoting cytokines by dendritic cells. Moreover, aloperine enhanced the conversion of Th17 into Treg via altering the pSTAT3/pSTAT5 ratio. Collectively, our study supported that aloperine possesses the capacity to affect Th17 differentiation and modulates Th17/Treg balance, thereby alleviating imiquimod (IMQ)-induced psoriasis in mice. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is characterized by the unresolved autoimmune inflammation and islet β cell destruction. The islet resident antigen-presenting cells (APCs) including dendritic cells and macrophages uptake and process the β cell-derived antigens to prime the autoreactive diabetogenic T cells. Upon activation, those autoreactive T cells produce copious amount of IFN-γ, TNF-α and IL-1β to induce β cell stress and death. Autoimmune attack and β cell damage intertwine together to push forward this self-destructive program, leading to T1D onset. However, β cells are far beyond a passive participant during the course of T1D development. Herein in this review, we summarized how β cells are actively involved in the initiation of autoimmune responses in T1D setting. Specifically, β cells produce modified neoantigens under stressed condition, which is coupled with upregulated expression of MHC I/II and co-stimulatory molecules as well as other immune modules, that are essential properties normally exhibited by the professional APCs. At the cellular level, this subset of APC-like β cells dynamically interacts with plasmacytoid dendritic cells (pDCs) and manifests potency to activate autoreactive CD4 and CD8 T cells, by which β cells initiate early autoimmune responses predisposing to T1D development. Overall, the antigen-presenting function of β cells helps to explain the tissue specificity of T1D and highlights the active roles of structural cells played in the pathogenesis of various immune related disorders. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is one of the most extensively studied autoimmune diseases, but the cellular and molecular mechanisms leading to T cell-mediated destruction of insulin-producing β cells are still not well understood. In this study, we show that regulatory T cells (Tregs) in NOD mice undergo age-dependent loss of suppressor functions exacerbated by the decreased ability of activated effector T cells to upregulate Foxp3 and generate Tregs in the peripheral organs. This age-dependent loss is associated with reduced intercellular communication mediated by gap junctions, which is caused by impaired upregulation and decreased expression of connexin 43. Regulatory functions can be corrected, even in T cells isolated from aged, diabetic mice, by a synergistic activity of retinoic acid, TGF-β, and IL-2, which enhance connexin 43 and Foxp3 expression in Tregs and restore the ability of conventional CD4+ T cells to upregulate Foxp3 and generate peripherally derived Tregs. Moreover, we demonstrate that suppression mediated by Tregs from diabetic mice is enhanced by a novel reagent, which facilitates gap junction aggregation. In summary, our report identifies gap junction-mediated intercellular communication as an important component of the Tregs suppression mechanism compromised in NOD mice and suggests how Tregs mediated immune regulation can be improved. [ABSTRACT FROM AUTHOR]

The presence of Foxp3+ regulatory CD4+ T cells in tumor lesions is considered one of the major causes of ineffective immune response in cancer. It is not clear whether intratumoral Treg cells represent Treg cells pre-existing in healthy mice, or arise from tumor-specific effector CD4+ T cells and thus representing adaptive Treg cells. The generation of Treg population in tumors could be further complicated by recent evidence showing that both in humans and mice the peripheral population of Treg cells is heterogenous and consists of subsets which may differentially respond to tumor-derived antigens. We have studied Treg cells in cancer in experimental mice that express naturally selected, polyclonal repertoire of CD4+ T cells and which preserve the heterogeneity of the Treg population. The majority of Treg cells present in healthy mice maintained a stable suppressor phenotype, expressed high level of Foxp3 and an exclusive set of TCRs not used by naive CD4+ T cells. A small Treg subset, utilized TCRs shared with effector T cells and expressed a lower level of Foxp3. We show that response to tumor-derived antigens induced efficient clonal recruitment and expansion of antigen-specific effector and Treg cells. However, the population of Treg cells in tumors was dominated by cells expressing TCRs shared with effector CD4+ T cells. In contrast, Treg cells expressing an exclusive set of TCRs, that dominate in healthy mice, accounted for only a small fraction of all Treg cells in tumor lesions. Our results suggest that the Treg repertoire in tumors is generated by conversion of effector CD4+ T cells or expansion of a minor subset of Treg cells. In conclusion, successful cancer immunotherapy may depend on the ability to block upregulation of Foxp3 in effector CD4+ T cells and/or selectively inhibiting the expansion of a minor Treg subset. [ABSTRACT FROM AUTHOR]

CD83 is a surface marker expressed on matured dendritic cells (DCs). It plays a pivotal role in the mediation of DC/T cell interaction and induction of T-cell activation. Previous studies have suggested that a soluble form of CD83 could suppress DC maturation and inhibit T-cell activation and, as a result, it can prevent paralysis associated with experimental autoimmune encephalomyelitis. Here, we explored its potential effect on allograft rejection in a fully major histocompatibility complex-mismatched murine skin transplantation model. A form of mouse soluble CD83 (CD83-Ig) fused the extracellular domain of murine CD83 with human IgG1 α Fc tail was purified from transfected COS-7 cell. It was found that the treatment of recipient mice with CD83-Ig significantly delayed allograft rejection. Especially, when T cells originated from recipients treated with CD83-Ig re-stimulated with donor-specific splenocytes, they showed a significant reduced responding capability as compared with that of originated from control recipients. In line with these results, a reduction for serum IFN- γ and IL-2 and a decreased mRNA expression of IFN- γ and IL-2 in allograft infiltrated immune cells were also observed. Our results suggest that CD83-Ig could be useful for the treatment of allograft rejection in combination with other therapeutic strategies. [ABSTRACT FROM AUTHOR]

The role of tumor-associated macrophages (TAMs), along with the regulatory mechanisms underlying distinct macrophage activation states, remains poorly understood in prostate cancer (PCa). Herein, we report that PCa growth in mice with macrophage-specific Ubc9 deficiency is substantially suppressed compared with that in wild-type littermates, an effect partially ascribed to the augmented CD8+ T cell response. Biochemical and molecular analyses revealed that signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of the UBC9 inhibitor 2-D08 promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade therapy. Together, our results demonstrate that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs by promoting STAT4-mediated macrophage activation and macrophage- CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis. [ABSTRACT FROM AUTHOR]

Highlights • Autophagy is an evolutionarily conserved cellular process that directs cytoplasmic proteins, organelles and microbes to lysosomes for degradation. • Regulatory T cells are a population of suppressor T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. • Autophagy is active in regulatory T cells and supports their linage stability and survival fitness. • Autophagy might be a promising target to manipulate regulatory T cell function in different disease settings. Abstract Autophagy is an evolutionarily conserved catabolic process that directs cytoplasmic proteins, organelles and microbes to lysosomes for degradation. It not only represents an essential cell-intrinsic mechanism to protect against internal and external stresses but also shapes both innate and adaptive immunity. Regulatory T cells (Tregs) are a developmentally and functionally distinct T cell subpopulation engaged in sustaining immunological self-tolerance and homeostasis. There is compelling evidence that autophagy is actively regulated in Tregs and serves as a central signal-dependent controller for Tregs by restraining excessive apoptotic and metabolic activities. In this review, we discuss how autophagy modulates the stability and functionality of Tregs in different disease settings, and provide a perspective on how manipulation of autophagy enables better control of immune response by targeting the generation of Tregs and the maintenance of their stability. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies demonstrate that both membrane B7-H4 and B7-H4-Ig fusion protein could inhibit T-cell responses. In the present study, we explored the potential effect of B7-H4-Ig on liver injury in a hepatitis mouse model induced by concanavalin A (ConA). A B7-H4-Ig construct was introduced into animals by the hydrodynamic gene delivery approach. It was found that ectopic expression of B7-H4-Ig could inhibit ConA-induced elevation of serum levels of ALT and AST, suppress liver necrosis and even mortality of mice. Furthermore, we observed that pretreatment of B7-H4-Ig dramatically decreased serum levels and the expression of mRNA for IL-2, IFN-γ and IL-4, but increased IL-10 in ConA-treated mice. Our results suggest that B7-H4-Ig may protect animals from liver injury induced by ConA, which could be associated with reduced serum levels for IL-2, IFN-γ and IL-4 as well as enhanced IL-10 production. [Copyright &y& Elsevier]

• DUSP regulates T cell activation and its effector function. • The impact of DUSP proteins on Treg development and functionality is dynamic. • DUSP regulates T cell senescence/exhaustion and involves in chronic immune related diseases. • DUSP proteins hold the potential to be promising diagnostic biomarkers and therapeutic targets in various immune related disease settings. The functional state of T cells is diverse and under dynamic control for adapting to the changes of microenvironment. Reversible protein phosphorylation represents an important post-translational modification that not only involves in the immediate early response of T cells, but also affects their functionality in the long run. Perturbation of global phosphorylation profile and/or phosphorylation of specific signaling nodes result in aberrant T cell activity. Dual specific phosphatases (DUSPs), which target MAPKs and beyond, have increasingly been emerged as a versatile regulator in T cell biology. Herein in this mini review, we sought to summarize and discuss the impact of DUSP proteins on the regulation of effector T cell activity, T cell polarization, regulatory T cell development and T cell senescence/exhaustion. Given the distinctive engagement of each DUSP member under various disease settings such as chronic infection, autoimmune disorders, cancer and age-related diseases, DUSP proteins likely hold the promise to become a druggable target other than the existing therapeutics that are predominantly by manipulating protein kinase activity. [ABSTRACT FROM AUTHOR]

Despite recent extensive studies, the molecular mechanism through which DCs induce allograft tolerance largely remains poorly understood. In the current study, we presented strong evidence supporting a role for IDO in DC-mediated allograft tolerance. Pre-treatment of recipient mice with IDO-transduced donor-specific BMDCs induced skin allograft tolerance in an antigen-dependent manner. Our data suggest that IDO-expressing DCs may regulate a delicate balance of cytokines that favors the differentiation of naïve CD4+ T cells into Tregs instead of CD4+ effector T cells. In addition, BMDCs with forced IDO expression also have higher capability to expand natural Tregs. In consistent with the observation of augmented Tregs detected in the recipient mice, the capacity for splenic T cell alloresponse was significantly reduced in recipient mice pre-treated with IDO-transduced BMDCs. Furthermore, the expression of inflammatory cytokines such as IL-2, IFN±γ, IL-6, IL-l 7A and IL-23p 19, in splenic T cells of these recipient mice, was significantly lower as compared to that of recipient mice pre-treated with either GFP-transduced BMDCs or untransduced BMDCs. [ABSTRACT FROM AUTHOR]