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Interleukin （IL）-15 plays an important role in natural killer （NK） and CD8＋ T-cell proliferation and function and is more effective than IL-2 for tumor immunotherapy. The trans-presentation of IL-15 by neighboring cells is more effective for NK cell activation than its soluble IL-15. In this study, the fusion protein dsNKG2D-IL-15, which consisted of two identical extracellular domains of human NKG2D coupled to human IL-15 via a linker, was engineered in Escherichia coll. DsNKG2D-IL- 15 could efficiently bind to major histocompatibility complex class I chain-related protein A （MICA） of human tumor cells with the two NKG2D domains and trans-present IL-15 to NK or CD8＋ T cells. We transplanted human gastric cancer （SGC-7901） cells into nude mice and mouse melanoma cells with ectopic expression of MICA （B 16BL6-MICA） into C57BL/6 mice. Then, we studied the anti-tumor effects mediated by dsNKG2D-IL-15 in the two xenografted tumor models. Human dsNKG2D-IL-15 exhibited higher efficiency than IL-15 in suppressing gastric cancer growth. Exogenous human dsNKG2D-IL-15 was centrally distributed in the mouse tumor tissues based on in vivo live imaging. The frequencies of human CD56＋ cells infiltrated into the tumor tissues following the injection of peripheral blood mononuclear cells into nude mice bearing human gastric cancer were significantly increased by human dsNKG2D-I L- 15 treatment. Human dsNKG2 D-I L- 15 also delayed the growth of transplanted melanoma （B 16BL6- MICA） by activating and recruiting mouse NK and CD8＋ T cells. The anti-melanoma effect of human dsNKG2D-IL-15 in C57BL/6 mice was mostly decreased by the in vivo depletion of mouse NK cells. These data highlight the potential use of human dsNKG2D-IL-15 for tumor therapy.

The programmed death 1 （PD-1） pathway is a way of inhibiting T-cell proliferation and cytokine production. This pathway is important for maintaining peripheral tolerance. Different mechanisms and cytokines are involved in this pathway. Herein, we show the contribution of endogenous TGF-β to increasing PD-1 expression after T cell receptor （TCR） activation.

G protein-coupled receptors （GPCRs） mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants. They are considered as the most successful therapeutic targets for a broad spectrum of diseases. Multiple sclerosis （MS） is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system （CNS）. It is the leading cause of non-traumatic disability in young adults. Great progress has been made over the past few decades in understanding the pathogenesis of MS. Numerous data from animal and clinical studies indicate that many GPCRs are critically involved in various aspects of MS pathogenesis, including antigen presentation, cytokine production, T-cell differentiation, T-cell proliferation, T-cell invasion, etc. In this review, we summarize the recent findings regarding the expression or functional changes of GPCRs in MS patients or animal models, and the influences of GPCRs on disease severity upon genetic or pharmacological manipulations. Hopefully some of these findings will lead to the development of novel therapies for MS in the near future.

CD4＋CD25＋FoxP3 ＋ regulatory T ceils （Tregs） are increased in patients with chronic hepatitis C, which may contribute to the sustained suppression of hepatitis C virus （HCV）-specific T-cell responses and viral persistence in HCV-infected individuals. We postulated that HCV core protein （HCVc） directly contributes to the expansion of Tregs in HCV-infected patients, and we provide evidence to support this hypothesis in the report. Peripheral blood mononuclear cells （PBMCs） and sera were collected from 87 treatment-naive chronic HCV-infected patients, CD4＋CD25＋ Tregs were measured by flow cytometry, and HCV RNA and HCVc levels were detected using qPCR and enzyme-linked immunosorbent assay （ELISA）, respectively. CD4＋, CD8＋, CD4＋CD25＋ and CD4＋CD25- T cells were purified from healthy donors and cultured with recombinant HCVc and Toll-like receptor （TLR） ligands. Flow cytometry was used to analyze cell proliferation, and ELISA was performed to measure cytokine production. In the 87 chronic HCV-infected patients, HCVc showed a significant correlation with HCV RNA and CD4＋CD25＋Tregs. Mechanistic studies showed that HCVc, together with anti-CD3 antibody, augmented CD4＋CD25＋ Treg proliferation, but inhibited CD4＋CD25- T-cell proliferation and IFN-γ production, in a dose-dependent and Treg-dependent manner. Moreover, unlike the TLR3 ligand （poly hC） and the TLR4 ligand （lipopolysaccharide, LPS）, the TLR2 ligand （lipoteichoic acid, LTA） and HCVc both inhibited TCR-induced CD4＋ T-cell proliferation and IFN-γ secretion in a Treg-dependent manner. These data indicate that HCVc, like other TLR2 ligands, triggers CD4＋CD25＋ Treg activation and expansion to inhibit host immune responses, which may play a critical role in viral persistence in HCV-infected patients.

Polyreactive innate-type B cells account for many B cells expressing self-reactivity in the periphery. Improper regulation of these B cells may be an important factor that underlies autoimmune disease. Here we have explored the influence of self-reactive innate B cells in the development of collagen-induced arthritis （CIA）, a mouse model of rheumatoid arthritis. We show that splenic marginal zone （MZ）, but not B- 1 B cells exhibit spontaneous IgM reactivity to autologous collagen II in na＇=＇ve mice. Upon immunization with heterologous collagen II in complete Freund＇s adjuvant the collagen-reactive MZ B cells expanded rapidly, while the B-1 B cells showed a modest anti-collagen response. The MZ B cells were easily activated by toll-like receptor （TLR） 4 and 9-1igands in vitro, inducing proliferation and cytokine secretion, implying that dual engagement of the B-cell receptor and TLRs may promote the immune response to self-antigen. Furthermore, collagen-primed MZ B cells showed significant antigen-presenting capacity as reflected by cognate T-cell proliferation in vitroand induction of IgG anti-collagen antibodies in vivo. MZ B cells that were deficient in complement receptors I and 2 demonstrated increased proliferation and cytokine production, while Fcy receptor lib deficiency of the cells lead to increased cytokine production and antigen presentation. In conclusion, our data highlight self-reactive MZ B cells as initiators of the autoimmune response in CIA, where complement and Fc receptors are relevant in controlling the self-reactivity in the cells.

Dear Editor, PD-L1, also known as CD274, plays a vital role in tumor cell related immune escape. It can be expressed on the cell surface of many solid tumors （Brahmer et al., 2012） and inhibits T cell proliferation and cytokine production by bind- ing to the Tcell surface receptor programmed death 1 （PD-1） or B7-1 （McClanahan et al., 2015）. In 2013, targeting PD-1/ PD-L1 signaling for cancer immunotherapy was selected as the No.1 scientific breakthrough of the year by the editors of Science. Interferons （IFNs） are a group of pleiotropic cytokines, demonstrated anti-viral, anti-tumor, and immune regulatory functions （York et al., 2015）. Type I interferon binds a heterodimeric receptor composed of IFNAR1 and IFNAR2. This activates a canonical JAK/STAT signaling pathway that ultimately induces a set of interferon-stimulated genes to exert its biological activity （Ejlerskov et al., 2015）. Recently, PD-L1 was reported to be downstream of IFN signaling in human oral squamous carcinoma, melanoma, and human acute myeloid leukemia blast cells （Chen et al., 2012; Furuta et al., 2014; Kronig et al., 2014）.

The mechanism underlying T cell-mediated fulminant hepatitis is not fully understood. In this study, we investigated whether myeloid derived suppressor cells （MDSCs） could prevent the concanavalin A （ConA）- induced hepatitis through suppressing T cell proliferation. We observed an increase in the frequencies of MDSCs in mouse spleen and liver at early stage of ConA treatment, implicating that the MDSCs might be involved in the initial resistance of mice against ConA- mediated inflammation. Subpopulation analysis showed that the MDSCs in liver of ConA-induced mice were mainly granulocytic MDSCs. Adoptive transfer of the bone marrow-derived MDSCs into ConA-treated mice showed that the MDSCs migrated into the liver and spleen where they suppressed T cell proliferation through ROS pathway. In addition, the frequencies of MDSCs in mice were also significantly increased by the treatment with immune suppressor glucocorticoids. Transfer of MDSCs into the regulatory T cell （Treg）- depleted mice showed that the protective effect of MDSCs on ConA-induced hepatitis is Treg-independent. In conclusion, our results demonstrate that MDSCs possess a direct protective role in T cell-mediated hepatitis, and increasing the frequency of MDSCs by either adoptive transfer or glucocorticoid treatment represents a potential cell-based therapeutic strategy for the acute inflammatory disease.

Progressive deterioration of innate and adaptive immune functions, a status termed ＇immunosenescence＇, is associated with the higher frequency and severity of diseases in the elderly, such as chronic infections, cancer and autoimmune disorders.1 Age-related immunosenescence can be characterized by a decrease in adaptive immunity and increase in low-grade chronic inflam- mation, also referred to as ＇inflamm- aging＇.2 This dysfunctional immunity is characterized by perturbations of the T- lymphocyte compartment, largely attrib- uted to thymus involution, shrinkage of the naive T-cell repertoire and oligoclonal expansions of memory T cells, particu- larly of CD8＋ effector memory subsets.3 Age and latent viral infections, especially human cytomegalovirus （CMV）, are both considered a driving force ofCD8＋ T-cell expansion and senescence, which is char- acterized by shortened telomeres, pro- gressive loss of costimulatory receptors, CD28 and CD27, and expression of sen- escence-associated surface markers, such as KLRG1 and the glycoepitope CD57, which also reflects the proliferative his- tory of cells.

Recent studies have revealed that autophagy, a fundamental intracellular process, plays many different roles in lymphocyte development and function. Autophagy regulates naive T-lymphocyte homeostasis, specifically by regulating mitochondrial quality and turnover, and is necessary for the proliferation of mature T cells. Autophagy also acts as a cellular death pathway in lymphocytes, both upon prolonged cytokine withdrawal and during acute antigen-receptor stimulation if improperly regulated. Furthermore, during HIV infection, hyperinduction of autophagy leads to massive T-cell death in uninfected CD4＋ T cells, and is rescued by inhibiting autophagic initiation. Constitutively high levels of autophagy in thymic epithelial cells are necessary for optimal processing and presentation of endogenous antigens, and required for proper positive and negative selection of developing thymocytes. Autophagy also promotes the survival of B lymphocytes, as well as the development of early B-cell progenitors. In B cells, autophagy is an alternative death pathway, as antigen-receptor stimulation in the absence of costimulation induces a potent autophagic death. Thus, autophagy plays a complex role in lymphocytes and is regulated during their lifespan to ensure a healthy immune system.

CD28 is one of the costimulatory molecules crucial for T-cell activation and thus has become an attractive target for therapeutic immunomodulation. Conventional strategies for blocking CD28 activity using monoclonal antibodies, Fab fragments, antagonistic peptide and fusion proteins, have apparent disadvantages such as inherent immunogenicity, unwanted Fc signaling, poor tissue penetration and bioinstability. Recent research has been directed toward the creation of non-natural, sequence-specific biomimetic oligomers with bioinspired structures that capture the amino-acid interface of the targeted proteins. One such family of molecules is the poly-N-substituted glycines or peptoids, which have close structural similarity to peptides but are essentially invulnerable to protease degradation. To screen for peptoids that specifically target CD28, we first designed and chemically synthesized 19 candidate peptoids based on molecular modeling and docking. Using the phage-displaying system that expresses the extracellular domain of the CD28 homodimer and contains the core B7-binding motif, a peptoid （No. 9） with a molecular formula of C21H29N307, was identified to display the highest binding activity to CD28. This peptoid not only inhibited the lymphocyte proliferation in vitro, but suppressed immunoresponses against alloantigens in vivo, and attenuated the graft-versus-host disease in a mouse bone-marrow transplantation model. These results suggested that peptoids targeting CD28 are effective agents for blocking the CD28-mediated costimulation and suitable for development of novel therapeutic approaches for diseases involving this pathway.