Huimin Fan

Induced Foxp3+ regulatory T cells: a potential new weapon to treat autoimmune and inflammatory diseases?

Foxp3(+) T regulatory cells (Tregs) consisting of natural and induced Treg subsets play a crucial role in the maintenance of immune homeostasis against self-antigen. The actions designed to correct defects in numbers or functions of Tregs may be therapeutic in the treatment of autoimmune diseases. While recent studies demonstrated that natural Tregs are instable and dysfunctional in the inflammatory condition, induced Tregs (iTregs) may have a different feature. Here we review the progress of iTregs, particularly focus on their stability and function in the established autoimmune diseases. The advantage of iTregs as therapeutics used under inflammatory conditions is highlighted. Proper generation and manipulation of iTregs used for cellular therapy may provide a promise for the treatment of many autoimmune and inflammatory diseases.

Autophagy facilitates TLR4- and TLR3-triggered migration and invasion of lung cancer cells through the promotion of TRAF6 ubiquitination.

Autophagy contributes to the pathogenesis of cancer, whereas toll-like receptors (TLRs) also play an important role in cancer development and immune escape. However, little is known about the potential interaction between TLR signaling and autophagy in cancer cells. Here we show that autophagy induced by TLR4 or TLR3 activation enhances various cytokine productions through promoting TRAF6 (TNF receptor-associated factor 6, E3 ubiquitin protein ligase) ubiquitination and thus facilitates migration and invasion of lung cancer cells. Stimulation of TLR4 and TLR3 with lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid [poly(I:C)] respectively triggered autophagy in lung cancer cells. This was mediated by the adaptor protein, toll-like receptor adaptor molecule 1 (TICAM1/TRIF), and was required for TLR4- and TLR3-induced increases in the production of IL6, CCL2/MCP-1 [chemokine (C-C motif) ligand 2], CCL20/MIP-3α [chemokine (C-C motif) ligand 20], VEGFA (vascular endothelial growth factor A), and MMP2 [matrix metallopeptidase 2 (gelatinase A, 72 kDa gelatinase, 72 kDa type IV collagenase)]. These cytokines appeared to be necessary for enhanced migration and invasion of lung cancer cells upon TLR activation. Remarkably, inhibition of autophagy by chemical or genetic approaches blocked TLR4- or TLR3-induced Lys63 (K63)-linked ubiquitination of TRAF6 that was essential for activation of MAPK and NFKB (nuclear factor of kappa light polypeptide gene enhancer in B-cells) pathways, both of which were involved in the increased production of the cytokines. Collectively, these results identify induction of autophagy by TLR4 and TLR3 as an important mechanism that drives lung cancer progression, and indicate that inhibition of autophagy may be a useful strategy in the treatment of lung cancer.

CD4+ T‐cell subsets in transplantation

The identification of T‐helper 9 (Th9), Th17, Th22 cells as distinct subsets of CD4+ T cells has extended the Th1/Th2 paradigm in the adaptive immunity. In the past decade, many studies in animal models and clinical transplantation have demonstrated that interleukin‐17 (IL‐17) is involved in allograft rejection. It appears that Th17 cells together with Th1 and Th2 cells play an important role in mediating allograft rejection. Here, we summarize our current knowledge on the contribution of Th1, Th2, Th9, Th17, Th22, and follicular T‐helper (Tfh) cells in allograft rejection. We also discuss the regulation of CD4+ T‐cell subsets by CD4+Foxp3+ regulatory T cells (Tregs) in the context of transplantation tolerance.

Adoptive Transfer of Induced-Treg Cells Effectively Attenuates Murine Airway Allergic Inflammation

Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4+FoxP3+) and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma.

BAFF promotes Th17 cells and aggravates experimental autoimmune encephalomyelitis.

Background BAFF, in addition to promoting B cell survival and differentiation, may affect T cells. The objective of this study was to determine the effect of BAFF on Th17 cell generation and its ramifications for the Th17 cell-driven disease, EAE. Methodology/Principal Findings Th17 cells were increased in BAFF-Tg B6 (B6.BTg) mice and decreased in B6.Baff−/− mice. Th17 cells in B6.Baff−/− mice bearing a BAFF Tg (B6.Baff−/−.BTg mice) were identical to those in B6.BTg mice, indicating that membrane BAFF is dispensable for Th17 cell generation as long as soluble BAFF is plentiful. In T + non-T cell criss-cross co-cultures, Th17 cell generation was greatest in cultures containing B6.BTg T cells and lowest in cultures containing B6.Baff−/− T cells, regardless of the source of non-T cells. In cultures containing only T cells, Th17 cell generation followed an identical pattern. CD4+ cell expression of CD126 (IL-6R α chain) was increased in B6.BTg mice and decreased in B6.Baff−/− mice, and activation of STAT3 following stimulation with IL-6 + TGF-β was also greatest in B6.BTg cells and lowest in B6.Baff−/− cells. EAE was clinically and pathologically most severe in B6.BTg mice and least severe in B6.Baff−/− mice and correlated with MOG35–55 peptide-induced Th17 cell responses. Conclusions/Significance Collectively, these findings document a contribution of BAFF to pathogenic Th17 cell responses and suggest that BAFF antagonism may be efficacious in Th17 cell-driven diseases.

Isolation of Purified and Live Foxp3+ Regulatory T Cells using FACS Sorting on Scatter Plot

There are no ideal ways to identify and isolate viable and purified Foxp3(+) regulatory T cells so far. Here we developed a novel procedure for the isolation of highly purified Foxp3(+) cells using flow cytometry. This method relies on an identification and sorting of the lymphoblast cell population identified on a scatter plot using flow cytometry. We confirmed that greater than 98% of the cells sorted using this technique expressed Foxp3 and displayed a potent suppressive activity. This method provides a valuable tool for the study of the T regulatory cell biology and their therapeutic manipulation.

miRNAs regulate stem cell self-renewal and differentiation

Stem cells undergo symmetric and asymmetric divisions to generate differentiated cells and more stem cells. The balance between self-renewal and differentiation of stem cells is controlled by transcription factors, epigenetic regulatory networks, and microRNAs (miRNAs). Herein the miRNA involvement in the regulation of stem cell self-renewal and differentiation is summarized. miRNA contribution to malignancy through regulating cancer stem cells is described. In addition, the reciprocal associations between miRNAs and epigenetic modifications in control of stem cell fate are discussed.

Nano-porous architecture of N-doped carbon nanorods grown on graphene to enable synergetic effects of supercapacitance

A novel nano-porous 3D architecture of N-doped carbon nanorods arrays grown on the surface of graphene has been prepared by carbonizing polyaniline/graphene oxide (PANI-GO) composite with PANI nanorod arrays on both sides of GO nanosheets. The obtained carbon materials are entirely composed of regularly grown carbon nanorods on graphene with height of about 100 nm and width about 30 nm, showing porous property due to the decomposition of PANI chains. The morphology of PANI grown on GO at the different growth stages was investigated to demonstrate the mechanism of the finally hierarchical architecture formation. Due to its large specific surface area and incorporation of the nitrogen groups into the carbon matrix, the obtained 3D carbon material enhances the ionic transport and the super-capacitance by synergetic effect of both double-layer and faradaic capacitances. This study provides a controllable approach to fabricate hierarchical carbon material based on conducting polymers and graphene oxide with promising applications in the high-rate electrode material of supercapacitors.

Tissue resident regulatory T cells: novel therapeutic targets for human disease

Over the past decade, the ability of regulatory T cells (Tregs) to suppress multiple types of immune cells has received tremendous attention. Mounting evidence has revealed that tissue resident Tregs control non-immunological processes of their target tissues and contribute to a plethora of human diseases. The identification of novel tissue-specific Tregs has highlighted their heterogeneity and complexity. This review summarizes the recent findings for visceral adipose tissue CD4+Foxp3+ regulatory T cells (VAT Tregs), muscle Tregs, bone Tregs and skin memory Tregs, with a focus on their unique functions in local tissues. This interpretation of the roles of tissue-specific Tregs and of their involvement in disease progression provides new insight into the discovery of potential therapeutic targets of human diseases.

Phenotypic and functional characteristic of a newly identified CD8+Foxp3−CD103+ regulatory T cells

TGF-β and Foxp3 expressions are crucial for the induction and functional activity of CD4(+)Foxp3(+) regulatory T (iTreg) cells. Here, we demonstrate that although TGF-β-primed CD8(+) cells display much lower Foxp3 expression, their suppressive capacity is equivalent to that of CD4(+) iTreg cells, and both Foxp3(-) and Foxp3(+) CD8+ subsets have suppressive activities in vitro and in vivo. CD8(+)Foxp3(-) iTreg cells produce little IFN-γ but almost no IL-2, and display a typical anergic phenotype. Among phenotypic markers expressed in CD8(+)Foxp3(-) cells, we identify CD103 expression particularly crucial for the generation and function of this subset. Moreover, IL-10 and TGF-β signals rather than cytotoxicity mediate the suppressive effect of this novel Treg population. Therefore, TGF-β can induce both CD8(+)Foxp3(-) and CD8(+)Foxp3(+) iTreg subsets, which may represent the unique immunoregulatory means to treat autoimmune and inflammatory diseases.