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The liver is a tolerogenic organ with exquisite mechanisms of immune regulation that ensure upkeep of local and systemic immune tolerance to self and foreign antigens, but that is also able to mount effective immune responses against pathogens. The immune privilege of liver allografts was recognized first in pigs in spite of major histo-compatibility complex mismatch, and termed the ＂liver tolerance effect＂. Furthermore, liver transplants are spontaneously accepted with only low-dose immunosuppression, and induce tolerance for non-hepatic co-transplanted allografts of the same donor. Although this immunotolerogenic environment is favorable in the setting of organ transplantation, it is detrimental in chronic infectious liver diseases like hepatitis B or C, malaria, schistosomiasis or tumorigenesis, leading to pathogen persistence and weak anti-tumor effects. The liver is a primary site of T-cell activation, but it elicits poor or incomplete activation of T cells, leading to their abortive activation, exhaustion, suppression of their effector function and early death. This is exploited by pathogens and can impair pathogen control and clearance or allow tumor growth. Hepatic priming of T cells is mediated by a number of local conventional and nonconventional antigen-presenting cells （APCs）, which promote tolerance by immune deviation, induction of T-cell anergy or apoptosis, and generating and expanding regulatory T cells. This review will focus on the communication between classical and nonclassical APCs and lymphocytes in the liver in tolerance induction and will discuss recent insights into the role of innate lymphocytes in this process.

The Ca2＋/calmodulin-dependent protein phosphatase calcineurin （CN）, a heterodimer composed of a catalytic subunit A and an essential regulatory subunit B, plays critical functions in various cellular processes such as cardiac hypertrophy and T cell activation. It is the target of the most widely used immunosuppressants for transplantation, tacrolimus （FKS06） and cyclosporin A. However, the structure of a large part of the CNA regulatory region remains to be determined, and there has been considerable debate concerning the regulation of CN activity. Here, we report the crystal structure of full-length CN （β isoform）, which revealed a novel autoinhibitory segment （AIS） in addition to the well-known autoinhibitory domain （AID）. The AIS nestles in a hydrophobic intersubunit groove, which over- laps the recognition site for substrates and immunosuppressant-immunophilin complexes. Indeed, disruption of this AIS interaction results in partial stimulation of CN activity. More importantly, our biochemical studies demonstrate that calmodulin does not remove AID from the active site, but only regulates the orientation of AID with respect to the catalytic core, causing incomplete activation of CN. Our findings challenge the current model for CN activation, and provide a better understanding of molecular mechanisms of CN activity regulation.

B cells are generally considered to be positive regulators of the immune response because of their capability to produce antibodies, including autoantibodies. The production of antibodies facilitates optimal CD4＋ T-cell activation because B cells serve as antigen-presenting cells and exert other modulatory functions in immune responses. However, certain B cells can also negatively regulate the immune response by producing regulatory cytokines and directly interacting with pathogenic T cells via cell-to-cell contact. These types of B Cells are defined as regulatory B （Breg） cells. The regulatory function of Breg cells has been demonstrated in mouse models of inflammation, cancer, transplantation, and particularly in autoimmunity. In this review, we focus on the recent advances that lead to the understanding of the development and function of Breg cells and the implications of B cells in human autoimmune diseases.

Neutrophil infiltration is a hallmark of alcoholic steatohepatitis; however, the underlying mechanisms remain unclear. We previously reported that chronic-plus-binge ethanol feeding synergistically induces hepatic recruitment of neutrophils, which contributes to liver injury. In this paper, we investigated the roles of invariant natural killer T （iNKT） cells in chronic-plus-binge ethanol feeding-induced hepatic neutrophil infiltration and liver injury. Wild-type and two strains of iNKT cell-deficient mice （CDld- and Ja18-deficient mice） were subjected to chronic-plus-binge ethanol feeding. Liver injury and inflammation were examined. Chronic-plus-binge ethanol feeding synergistically increased the number of hepatic iNKT cells and induced their activation, compared with chronic feeding or binge alone, iNKT cell-deficient mice were protected from chronic-plus-binge ethanol-induced hepatic neutrophil infiltration and liver injury. Moreover, chronic-plus-binge ethanol feeding markedly upregulated the hepatic expression of several genes associated with inflammation and neutrophil recruitment in wild-type mice, but induction of these genes was abrogated in iNKT cell-deficient mice. Importantly, several cytokines and chemokines （e.g., MIP-2, MIP-1, IL-4, IL-6 and osteopontin） involved in neutrophil infiltration were upregulated in hepatic NKT cells isolated from chronic-plus-binge ethanol-fed mice compared to pair-fed mice. Finally, treatment with CDld blocking antibody, which blocks iNKT cell activation, partially prevented chronic-plus-binge ethanol-induced liver injury and inflammation. Chronic-plus-binge ethanol feeding activates hepatic iNKT cells, which play a critical role in the development of early alcoholic liver injury, in part by releasing mediators that recruit neutrophils to the liver, and thus, iNKT cells represent a potential therapeutic target for the treatment of alcoholic liver disease.

Hedyotis hedyotidea has been used in traditional Chinese medicine for the treatment of autoimmune diseases. However, the mechanisms underlying for the effect remain unknown. We previously showed that, among 11 compounds extracted from H hedyotidea, betulin produced the strongest suppressive effect on T cell activation. Here, we examined the hepatoprotective effects of betulin against acute autoimmune hepatitis in mice and the mechanisms underlying the effects. Freshly isolated mouse splenocytes were stimulated with concanavalin A （Con A, 5 pg/mL） in the presence of betulin, the cell proliferation was assessed with CSFE-dilution assay. Mice were injected with betulin （10, 20 mg.kg-1.d-1, ip） for 3 d. One hour after the last injection, the mice were injected with Con A （15 mg/kg, iv） to induce acute hepatitis. Blood samples and liver tissues were harvested at 10 h after Con A injection, and serum transaminase levels and liver histopathology were detected; serum levels of proinflammatory cytokines, hepatic T lymphocyte ratios, and functional statuses of conventional T and NKT cells were also analyzed. Betulin （16 and 32 μmol/L） dose-dependently suppressed the proliferation of Con A-stimulated mouse splenocytes in vitro. In Con A-challenged mice, preinjection with betulin （20 mg.kg-1.d-1） significantly decreased the levels of proinflammatory cytokines IFN-γ, TNF-α and IL-6, and ameliorated liver injury. Furthermore, pretreatment with betulin （20 mg-kg-1.d-1） significantly inhibited the Con A-induced activation of NKT and conventional T cells, and decreased production of proinflammatory cytokines IFN-γ, TNF-α and IL-6 in these two cell populations. Betulin has immunornodulatory effect on overly activated conventional T and NKT cells and exerts hepatoprotective action in mouse autoimmune hepatitis. The findings provide evidence for the use of H hedyotidea and its constituent betulin in the treatment of autoimmune diseases.

Hyperhomocysteinemia （HHcy） accelerates atherosclero- sis by increasing proliferation and stimulating cytokine secretion in Tcells. However, whether homocysteine （Hcy）- mediated T cell activation is associated with metabolic reprogramming is unclear. Here, our in vivo and in vitro studies showed that Hcy-stimulated splenic T-cell activa- tion in mice was accompanied by increased levels of mitochondrial reactive oxygen species （ROS） and calcium, mitochondrial mass and respiration. Inhibiting mitochon- drial ROS production and calcium signals or blocking mitochondrial respiration largely blunted Hcy-induced T-cell interferon y （IFN-v） secretion and proliferation. Hcy also enhanced endoplasmic reticulum （ER） stress in T cells, and inhibition of ER stress with 4-phenylbutyric acid blocked Hcy-induced T-cell activation. Mechanistically, Hcy increased ER-mitochondria coupling, and uncou- pling ER-mitochondria by the microtubule inhibitor nocodazole attenuated Hcy-stimulated mitochondrial reprogramming, IFN-y secretion and proliferation in T cells, suggesting that juxtaposition of ER and mitochon-dria is required for Hcy-promoted mitochondrial function and T-cell activation. In conclusion, Hcy promotes T-cell activation by increasing ER-mitochondria coupling and regulating metabolic reprogramming.

Aim： To investigate the immunomodulating activity of astragalosides, the active compounds from a traditional tonic herb Astragalus membranaceus Bge, and to explore the molecular mechanisms underlying the actions, focusing on CD45 protein tyrosine phosphatase （CD45 PTPase）, which plays a critical role in T lymphocyte activation. Methods： Primary splenocytes and T cells were prepared from mice. CD45 PTPase activity was assessed using a colorimetric assay. Cell proliferation was measured using a [3H]-thymidine incorporation assay. Cytokine proteins and mRNAs were examined with ELISA and RT-PCR, respectively. Activation markers, including CD25 and CD69, were analyzed using flow cytometry. Activation of LCK （Tyr505） was detected using Western blot analysis. Mice were injected with the immunosuppressant cyclophosphamide （CTX, 80 mg/kg）, and administered astragaloside II （50 mg/kg）. Results： Astragaloside I, II, III, and IV concentration-dependently increased the CD45-mediated of pNPP/OMFP hydrolysis with the ECso values ranged from 3.33 to 10.42 pg/mL. Astragaloside II （10 and 30 IJg/mL） significantly enhanced the proliferation of primary splenocytes induced by ConA, alloantigen or anti-CD3. Astragaloside II （30 pg/mL） significantly increased IL-2 and IFN-y secretion, upregulated the mRNA levels of IFN-~ and T-bet in primary splenocytes, and promoted CD25 and CD69 expression on primary CD4~ T cells upon TCR stimulation. Furthermore, astragaloside II （100 ng/mL） promoted CD45-mediated dephosphorylation of LCK （Tyr505） in primary T cells, which could be blocked by a specific CD45 PTPase inhibitor. In CTX-induced immunosuppressed mice, oral administration of astragaloside II restored the proliferation of splenic T cells and the production of IFN-γ and IL-2. However, astragaloside II had no apparent effects on B cell proliferation. Conclusion： Astragaloside II enhances T cell activation by regulating the activity of CD45 PTPase, which may explain why Astragalus membranaceus Bge is used as a tonic herb in treating immunosuppressive diseases.

Dear Editor, Genetically engineered T cell therapy is a promising new strategy to combat cancer. The chimeric antigen re- ceptor-expressing T cell （CART） approach has achieved success in clinical trials of patients with non-solid tu- mors [1, 2]. Some limitations nevertheless have emerged. Among them are restriction of the CARs to the cell surface and the risks associated with retroviral integra- tion in the genome [3, 4]. A recent development is the design of bispecific T-cell engagers （BiTEs）, a class of artificial bispecific antibodies that are composed of two single-chain variable fragments （scFv）, one specific for a T-cell-specific molecule, usually CD3, and the other spe- cific for a tumor-associated antigen [5-8]. BiTE therapy is nevertheless limited by the short half-life of antibod- ies, the lack of endogenous effector T cells in patients with advanced cancer, and severe adverse effects such as cytokine release syndrome caused by T cell activation [9-11 ]. In the current study, we present a novel secretable BITE, ~tHER2/CD3, which consists of HER2-specific scFv 4D5, CD3-specific scFv OKT3, and flexible linkers （Figure I A）. We show that aHER2/CD3 specifically tar- gets HERT tumor cells, such as those found in gastric cancer and breast cancer [12], and CDT human T cells.

Highly pathogenic avian influenza H5N 1 epidemics are a significant public health hazard. Genetically engineered H5N 1 viruses with mammalian transmission activity highlight the potential risk of a human influenza H5N 1 pandemic. Understanding the underlying principles of the innate immune system in response to influenza H5N 1 viruses will lead to improved prevention and control of these potentially deadly viruses, γδT cells act as the first line of defense against microbial infection and help initiate adaptive immune responses during the early stages of viral infection. In this study, we investigated the molecular mechanisms of γδ T cells in response to influenza H5N1 viral infection, We found that recombinant hemagglutinin （rHA） derived from three different strains of influenza H5N 1 viruses elicited the activation of γδ T cells cultured in peripheral blood mononuclear cells （PBMCs）. Both the cell surface expression of CD69, an early activation marker on γδ T cells, and the production of interferon-y （IFN-y） were significantly increased. Notably, the rHA protein-induced γδ T-cell activation was not mediated by TCRγδ, NKG2D or pattern recognition receptors （PRRs） or NKp46 receptors. The interaction of rHA proteins with sialic acid receptors may play a critical role in γδ T-cell activation. Our data may provide insight into the mechanisms underlyingγδT-cell activation in response to infection with H5N1 viruses.

T-cell regulation by CD52-expressing CD4 T cells appears to operate by two different and possibly synergistic mechanisms. The first is by its release from the cell surface of CD4 T cells that express high levels of CD52 that then binds to the inhibitory sialic acid-binding immunoglobulin-like lectins-lO （Siglec-lO） receptor to attenuate effector T-cell activation by impairing phosphorylation of T-cell receptor associated Ick and zap-70. The second mechanism appears to be by crosslinkage of the CD52 molecules by an as yet unidentified endogenous ligand that is mimicked by a bivalent anti-CD52 antibody that results in their expansion.