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Close-to-nature management (CTNM) has been proposed as a promising forestry management approach to improve the structure and quality of forests, which integrates wood production and ecological service functions. Research on the effect of CTNM on the univariate and bivariate distribution of the spatial structure of forest stands provides a scientific basis for the evaluation of CTNM implemented in forestry. Here, we analyzed and compared the spatial-structure characteristics of Masson pine (Pinus massoniana) plantations (young, middle-age, and near-mature stages) under CTNM 8 years after selective cutting and unmanaged control. We used univariate and bivariate distribution of three spatial-structure parameters: mingling (M), dominance (U), and uniform-angle index (W). Results showed that the effect of CTNM on spatial structure was more remarkable in middle-aged and near-mature Masson pine forests compared with the young forest. CTNM significantly improved mingling degree and promoted the horizontal distribution, thereby changing from a cluster to a random distribution. Moreover, CTNM improved the proportion of trees with a high mixing degree and random distribution and the proportion of trees having a micro-structure of random distribution with a high degree of mixture and dominance with a high degree of mixture in middle-aged and near-mature Masson pine forest. Overall, the implementation of CTNM 8 years ago showed a positive effect on the improvement of the spatial structure of Masson pine forest, but the present spatial structure is suboptimal. Further implementation of CTNM to adjust the mingling and uniform-angle index is necessary, and CTNM according to this method of frequency distribution of stand structure parameters can improve the success of forest management.

Objective:To perform a network meta-analysis(NMA) of randomized controlled trials of topical therapies for plaque psoriasis, especially some new drugs for psoriasis.Our objective was to establish the effectiveness, tolerability and safety of topical treatments for people with chronic plaque psoriasis. Methods: We systematically searched PubMed, Cochrane Library and Embase databases to identify randomized controlled trials of topical therapies in adult patients with plaque psoriasis.Due to older literature were not able to included some novel topical therapies,we only searched the article that published between 01 January 2010 and 20 February 2022 in English. The primary efficacy assessment criteria were treatment success(the number of patients who achieved Physician’s Global Assessment or Investigator’s Global Assessment of a score of clear or nearly clear(PGA0/1,IGA0/1)) and the paitents who reported adverse events (AEs) at 4-12 weeks. Secondary criteria were the propotion of patients with 75 % reductions in Psoriasis Area and Severity Index (PASI 75) and the number of patients who reported drug withdrawal due to adverse events at 4-12 weeks.We combined with hierarchical cluster analyses to consider efficacy, safety and tolerability. Results: The review included 24 randomized controlled trials of topical treatments for plaque psoriasis with 9748 participants. This network meta-analysis showed that topical treatments were significantly more effective than placebo at 4-12weeks, in addition to tofacitinib ointment. hierarchical cluster analyses shows that topical calcipotriene and betamethasone dipropionate(Cal/BD),roflumilast,betamethasone,halobetasol-propionate and tazarotene(HP/TAZ), halobetasol were comparable with respect to high short-term efficacy, safety and tolerability, especially Cal/BD and roflumilast.

Protein kinase C (PKC)-θ has been shown to be a critical TCR signaling molecule that promotes the activation and differentiation of naive T cells into inflammatory effector T cells. In this study, we demonstrate that PKC-θ–mediated signals inhibit inducible regulatory T cell (iTreg) differentiation via an AKT-Foxo1/3A pathway. TGF-β–induced iTreg differentiation was enhanced in PKC-θ−/− T cells or wild-type cells treated with a specific PKC-θ inhibitor, but was inhibited by the PKC-θ activator PMA, or by CD28 crosslinking, which enhances PKC-θ activation. PKC-θ−/− T cells had reduced activity of the AKT kinase, and the expression of a constitutively active form of AKT in PKC-θ−/− T cells restored the ability to inhibit iTreg differentiation. Furthermore, knockdown or overexpression of the AKT downstream targets Foxo1 and Foxo3a was found to inhibit or promote iTreg differentiation in PKC-θ−/− T cells accordingly, indicating that the AKT-Foxo1/3A pathway is responsible for the inhibition of iTreg differentiation of iTregs downstream of PKC-θ. We conclude that PKC-θ is able to control T cell-mediated immune responses by shifting the balance between the differentiation of effector T cells and inhibitory Tregs.

Survival of CD4+CD8+ double-positive (DP) thymocytes plays a critical role in shaping the peripheral T cell repertoire. However, the mechanisms responsible for the regulation of DP thymocyte lifespan remain poorly understood. In this work, we demonstrate that T cell factor (TCF)-1 regulates DP thymocyte survival by upregulating RORγt. Microarray analysis revealed that RORγt was significantly downregulated in TCF-1−/− thymocytes that underwent accelerated apoptosis, whereas RORγt was greatly upregulated in thymocytes that had enhanced survival due to transgenic expression of a stabilized β-catenin (β-catTg), a TCF-1 activator. Both TCF-1−/− and RORγt−/− DP thymocytes underwent similar accelerated apoptosis. Forced expression of RORγt successfully rescued TCF-1−/− DP thymocytes from apoptosis, whereas ectopically expressed TCF-1 was not able to rescue the defective T cell development because of the lack of RORγt-supported survival. Furthermore, activation of TCF-1 by stabilized β-catenin was able to enhance DP thymocyte survival only in the presence of RORγt, indicating that RORγt acts downstream of TCF-1 in the regulation of DP thymocyte survival. Moreover, β-catenin/TCF-1 directly interacted with the RORγt promoter region and stimulated its activity. Therefore, our data demonstrated that TCF-1 enhances DP thymocyte survival through transcriptional upregulation of RORγt, which we previously showed is an essential prosurvival molecule for DP thymocytes.

More than 80% of thymocytes are CD4+CD8+ double positive (DP) cells which subject to positive/negative selection. The lifespan of DP thymocytes is critical in shaping the peripheral T cell repertoire essential for mounting immune responses against foreign, but not self, antigens. During T cell maturation, if the first round of T cell receptor (TCR) α chain rearrangement fails to generate a productive T cell receptor, DP cells start another round of α chain rearrangement until positive selection or cell death intervenes. Thus, the lifespan of DP cells determines how many rounds of α chain rearrangement can be carried out, and influences the likelihood of completing positive selection. The anti-apoptotic protein Bcl-xL is the ultimate effector regulating DP cell survival, and several transcription factors critical for T cell development, such as TCF-1, E proteins, c-Myb, and RORγt, regulate DP survival via a Bcl-xL-dependent pathway. However, the relationship between these transcription factors in this process is largely unclear. Recent results are revealing an interactive network among these critical factors during regulation of DP thymocyte survival. This review will discuss how these transcription factors potentially work together to control DP thymocyte survival that is critical for successful completion of T cell development.

As a testament to the importance of CD24, researchers with diverse interests, including adaptive immunity, inflammation, autoimmune diseases and cancer, have encountered CD24. CD24 is overexpressed in many cancers and appears oncogenic. In the adaptive immune response, CD24 is a redundant costimulatory molecule in costimulation-rich lymphoid organs but is essential in selected target organs tested, such as brain and skin. More recent studies suggest it may have a role in discriminating danger and pathogen-associated molecular patterns by dendritic cells. The biology of CD24 is intriguing but poorly understood. Here we summarize the major findings associated with CD24 to stimulate new ideas for further research that may reveal the underlying link among the diverse processes mediated by CD24.

The identification of individuals genetically susceptible to cancer calls for preventive measures to minimize the cancer risk in these high-risk populations. Immune prevention is made necessary by the anticipated health threat, but lack of enough high-affinity T cells against tumor-associated antigens and the unpredictability of tumor antigens make antigen-based immune prevention untenable for cancer. To address this issue, we explored a non-antigen-based cancer immune prevention strategy using the transgenic adenocarcinoma of mouse prostate model that spontaneously develops prostate cancer with 100% penetrance. We show that targeted mutation of the lymphotoxin α ( LT α) gene efficiently rescued tumor-reactive T cells, drastically reduced cancer incidence, and almost completely ablated metastasis. Remarkably, short-term treatments with the fusion protein consisting of constant region of IgG and extracellular domain of lymphotoxin β receptor (LTβRIg) interrupted clonal deletion, reduced the size of the primary cancer, and completely prevented metastasis later in life. Our data demonstrated the value of non-antigen-based immune prevention for those with a genetic predisposition to cancer.

Human leukocyte antigen G (HLA-G) is one of the molecules implicated in immunotolerance. To investigate the role of HLA-G in primary cutaneous malignant melanoma (CMM), a series of 47 skin melanocytic lesions were immunohistochemically evaluated. The correlation between HLA-G expression and CMM clinicohistopathological data and Bcl-2 expression was also analyzed. HLA-G expression was detected in a variety of cell types. No significant difference in HLA-G expression was observed between malignant and non-malignant melanocytic lesions. HLA-G expression was significantly correlated with the inflammatory infiltration and Bcl-2 expression, whereas no significant correlation with ulceration, tumor thickness, clinical stage, histopathological subtypes were observed. HLA-G expression may be the result of host immune reaction in tumor microenvironment rather than a malignant feature of CMM.

To investigate the role of progesterone receptor (PR) expression in malignant melanoma (MM), PR and proliferative cell nuclear antigen (PCNA) expression were immunohistochemistrically evaluated in a series of 35 specimens of MM, and the correlation between the immunohistochemistrical findings and clinicopathological data was also analyzed. PR expression was detected in 25.7% (9/35) of the patients with MM. No PR expression was observed in nevi. PR expression was inversely correlated with PCNA expression (r=-0.353, P=0.026). PR expression was slightly increased in females, subjects aged under 55 y, those with ulceration, non-acral subtype and diagnosis delay longer than 1 y, but the difference was not statistically significant. Selective expression of progesterone receptor in malignant melanoma might be correlated with inhibited tumor growth.

A large number of risk alleles have been identified for multiple sclerosis (MS). However, how genetic variations may affect pathogenesis remains largely unknown for most risk alleles. Through direct sequencing of CD24 promoter region, we identified a cluster of 7 new single nucleotide polymorphisms in the CD24 promoter. A hypermorphic haplotype consisting of 3 SNPs was identified through association studies consisting of 935 control and 764 MS patients (P=0.001, odds ratio 1.3). The variant is also associated with more rapid progression of MS (P=0.016, log rank test). In cells that are heterozygous for the risk allele, chromatin immunoprecipitation revealed that risk allele specifically bind to a transcription factor SP1, which is selectively required for the hypermorphic promoter activity of the variant. In MS patients, the CD24 transcript levels associate with the SP1-binding variant in a dose-dependent manner (P=7x10(-4)). Our data revealed a potential role for SP1-mediated transcriptional regulation in MS pathogenesis.

T cells must undergo two critical differentiation processes before they become competent effectors that can mediate actual immune responses. Progenitor T cells undergo defined stages of differentiation in the thymus, which include positive and negative selection, to generate a repertoire of T cells that will respond to foreign but not self antigens. When these immunocompetent T cells first migrate out of thymus into peripheral lymphoid tissues, they are naive and are unable to mediate immune responses. However, upon antigen encounter, peripheral CD4+ naive T cells undergo another differentiation process to become armed effector T cells including Th1, Th2, Th17 or regulatory T cells, all of which are capable of regulating immune responses. A canonical Wnt/β-catenin/T cell factor (TCF) pathway has been shown to regulate T cell differentiation in both the thymus and in peripheral lymphoid tissues. Dysfunction of this pathway at any stage of T cell differentiation could lead to severe autoimmunity including experimental autoimmune encephalomyelitis or immune deficiency. Understanding the role played by β-catenin/TCF-1 in T cell differentiation will facilitate our understanding of the mechanisms that regulate T cell function and assist in identifying novel therapy targets for treating both autoimmune and immune diseases. Therefore, in this review, we will focus on the function of β-catenin/TCF-1 pathway in the regulation of thymic and peripheral T cell differentiation processes.

Severe liver injury that occurs when immune cells mistakenly attack an individual's own liver cells leads to autoimmune hepatitis. In mice, acute hepatitis can be induced by concanavalin A (ConA) treatment, which causes rapid activation of CD1d-positive natural killer (NK) T cells. These activated NKT cells produce large amounts of cytokines, which induce strong inflammation that damages liver tissues. Here we show that PKC-θ(-/-) mice were resistant to ConA-induced hepatitis due to essential function of PKC-θ in NKT cell development and activation. A dosage of ConA (25 mg/kg) that was lethal to wild-type (WT) mice failed to induce death resulting from liver injury in PKC-θ(-/-) mice. Correspondingly, ConA-induced production of cytokines such as IFNγ, IL-6, and TNFα, which mediate the inflammation responsible for liver injury, were significantly lower in PKC-θ(-/-) mice. Peripheral NKT cells had developmental defects at early stages in the thymus in PKC-θ(-/-) mice, and as a result their frequency and number were greatly reduced. Furthermore, PKC-θ(-/-) bone marrow adoptively transferred to WT mice displayed similar defects in NKT cell development, suggesting an intrinsic requirement for PKC-θ in NKT cell development. In addition, upon stimulation with NKT cell-specific lipid ligand, peripheral PKC-θ(-/-) NKT cells produced lower levels of inflammatory cytokines than that of WT NKT cells, suggesting that activation of NKT cells also requires PKC-θ. Our results suggest PKC-θ is an essential molecule required for activation of NKT cell to induce hepatitis, and thus, is a potential drug target for prevention of autoimmune hepatitis.

Background NKT cell is a population of unconventional T cells that mediate both innate and adaptive T cell responses. Since NKT cells are most abundant in the liver, much of NKT biology has been learnt from studies of NKT cells isolated from liver. This is a cumbersome procedure with variations in cell yield. Results Based on recent evidence that NKT cells reside in liver vascular compartment, we developed a simple method to isolate NKT cells by perfusion with PBS-containing 10 mM of EDTA. The number and cell surface phenotype of liver NKT cells recovered by perfusion and by the traditional method were comparable. The yield of other lymphocytes was also comparable. Conclusion/Significance Our data demonstrated that liver lymphocytes can be efficiently isolated by simple perfusion. These data provide a convenient method to isolate liver lymphocyte while preserving liver tissue for other analysis.

This study investigated the growth-regulating effects of progesterone (Prog) on nPR-negative malignant melanoma cells and the possible mechanisms. A375 and A875 cells were cultured and treated with Prog of different concentrations. For signal transduction pathway studies, the cells were pretreated with Prog receptor antagonist (RU486, 1 x 10(-7) mol/L) or MAPK inhibitor (U0126, 5 x 10(-6) mol/L) for 1 h and then co-incubated with prog (10(-9) mol/L) for another 24 h. Indirect immunofluorescence assay, MTT, flow cytometry and Western blotting were used for assessing the nPR expression, cell growth, cell apoptosis and ERK1/2 Phosphorylation, respectively. Our results showed that lower progesterone concentration promoted the proliferation of both A375 and A875 cells, but this growth-stimulatory effect decreased at progesterone concentration of 1 x 10(-7) mol/L or higher. The response could be abolished by MAPK inhibitor U0126, but could not be blocked by progesterone antagonist RU486. Flow cytometry exhibited that high concentration ([Symbol: see text]1 x 10(-7) mol/L) progesterone increased the apoptosis of the two cells in a dose-dependent manner. The level of ERK1/2 phosphorylation was increased by a lower progesterone concentration, but reduced by a higher concentration (1 x 10(-6) mol/L). These results suggest progesterone exerts growth-regulating effects on nPR-negative tumor cells through a non-genomic mechanism.

ObjectiveTo study the effect of tumor necrosis factor-α (TNF-α) antagonist (etanercept) treatment on the peripheral T cell reactivity of patients with ankylosing spondylitis (AS).MethodsPeripheral blood mononuclear cells were collected from 40 patients with AS at baseline, after 2 and 6 weeks of etanercept treatment or placebo treatment, and from healthy controls. The number of cells secreting various cytokines was detected by enzyme linked immunospot. Serum soluble interleukin 2 (IL-2) receptor level was measured by ELISA. T cell proliferation was assayed with the WST-1 live cell-staining method. The myeloid dendritic cell (mDC) and regulatory T cell (Treg) levels were analyzed by fluorescence activated cell sorting.ResultsAfter 2 and 6 weeks of etanercept treatment, the number of TNF-α-secreting monocytes decreased. Although the T cell proliferation rate remained stable, the number of T cells secreting IL-2 and interferon-γ under anti-CD3/anti-CD28 stimulation was significantly decreased. The level of serum soluble IL-2R (sIL-2R), a T cell activation marker, also declined. The changes in T cell reactivity were correlated with a significant increase in MHC Class II-positive mDC cells in circulation. An increase in Treg cell numbers was also observed.ConclusionThe anti-TNF-α therapy blockaded MHC Class II-positive mDC maturation, enhanced regulatory T cell levels, and suppressed the functions of effector T cells. The reduced T cell reactivity could contribute to the efficacy of the TNF-α antagonist therapy in patients with AS.

We demonstrate here that PKC-θ is a critical molecule to maintain immunological balance by shifting the ratio of inflammatory Th17 and inhibitory Treg cells. TGFβ-induced T regulatory cell (iTreg) differentiation was enhanced in naive PKC-θ -/- T cells or WT cells treated with a specific PKC-θ inhibitor. PKC-θ -/- T cells had reduced activity of the AKT kinase, and the expression of a constitutively active form of AKT in PKC-θ -/- T cells restored ability to inhibit iTreg differentiation. Furthermore, knockdown or overexpression of the AKT downstream targets FoxO1 and FoxO3a was found to inhibit or promote iTreg differentiation in PKC-θ -/- T cells, indicating that the AKT-FoxO1/3A pathway plays an inhibitory role in the differentiation of iTreg downstream of PKC-θ. In the other hand, we show that naive PKC-θ -/- T cells were defective in Th17 differentiation in vitro, whereas in vitro differentiation of Th1 and Th2 appeared normal. PKC-θ -/- T cells had notably lower levels of Stat3, a transcription factor required for Th17 differentiation. PKC-θ-mediated activation of the Stat3 promoter was inhibited by dominant negative AP-1 and IκB kinase β mutations, but stimulated by WT AP-1 and IκB kinase β, suggesting that PKC-θ stimulates Stat3 transcription via the AP-1 and NF-κB pathways. We conclude that PKC-θ is able to control T cell-mediated immune responses by shifting the balance between the differentiation of Th17 inflammatory and regulatory T cells.