Interferon regulatory factor 4 (IRF4) is an evolutionarily conserved regulatory molecule that is expressed in varying levels at key stages of differentiation of many immune cells. In terms of its role in the differentiation of innate immune cell lineages, IRF4 is one of the key transcription factors regulating M2-like macrophage polarization and differentiation of both monocyte-derived DC and conventional DC 2 (cDC2). On the other hand, on the differentiation and fate determination of adaptive immune cell subgroups, IRF4 plays a broad role and controls all levels of differentiation of these immune cell subgroups in that IRF4 regulates the differentiation of the naive CD4⁺ T cells into various subsets (Th1, Th2, Th9, Th17, Treg, and follicular helper T cell ［Tfh］). In addition, it also dictates the differentiation of naive CD8⁺ T cells into effector cells. At the same time, IRF4 also regulates B cell differentiation cycle and plasma cell function, thereby affecting humoral immunity. The recent progress in the study of IRF4's involvement in the regulation of immune cell lineage differentiation and fate determination is summarized in this review.

This study aims to develop a method to efficiently and stably induce the differentiation and expansion of human myeloid-derived suppressor cells (MDSC) in vitro and provide new experimental technology for the study of the function and mechanism of human MDSC. For this purpose, PBMC of healthy volunteers were isolated with Ficoll density gradient centrifugation. Next, monocytes were separated by anchoring technique. PBMC or monocytes were stimulated with GM-CSF and IL-6 (10, 20, 40, 80 ng/mL each) for 4, 7, 14, and 21 days before co-culturing with PBMC for 3 days. The proliferation of CD33⁺ MDSC and T cells and the proportion of CD3⁺IFN-γ⁺ T cells were detected by FACS. The results showed that the PBMC or monocytes were induced to differentiate to less CD33⁺MDSC by conventional methods. However, by improved methods, the monocytes cultured with GM-CSF and IL-6 (each 80 ng/mL) for 14 days (refreshing the culture solution every 4-5 days) were induced to differentiate more efficiently into a higher proportion of CD33⁺MDSC, which showed significant inhibition of T cell proliferation and IFN-γ secretion. This study suggests that with the improved method, the monocytes are efficiently induced to differentiate into CD33⁺ MDSC, which has significant suppressive function.

Mesenchymal stromal cell (MSC) has immunosuppressive properties, and may inhibit inflammatory and autoimmune diseases by regulating various immune cell responses. T cells recognize a variety of pathogens and tumor cells, mediate immune responses, and maintain immune memory and self-tolerance. Meanwhile, T cells are also a major driver of various inflammatory and autoimmune diseases. Different subsets of T cells play different roles in the immune responses. MSC establishes direct or indirect contact with T cells through surface molecules and secretion of soluble factors and produces inhibitory or promotive effects after the interaction. On one hand, MSC mediates the inhibition of T cell proliferation to achieve immunosuppressive effects. On the other hand, MSC corrects the balance between pro-inflammatory factors (such as IFN-γ and TNF-α) and anti-inflammatory factors (such as IL-10) by regulating the differentiation of various T cell subsets. This article reviews the mechanisms by which MSC regulates the differentiation of various T cell subsets.

During the global pandemic of COVID-19, memory T cells have drawn increasing research attention because of their superior antiviral capacity. The latest research demonstrates that certain APC and cytokines in the microenvironment are required for the differentiation and effector responses of memory CD4⁺ T cells via tightly modulated intracellular transcription factors and energy metabolism. This review summarizes and discusses the key mechanisms underlying the development, long-term maintenance, and secondary immune responses of memory CD4⁺ T cells. Precise regulation of their number and functions in different types of diseases will be a big challenge in the future.

Runt related transcription factor (RUNX) is the main regulator during embryonic development and is essential for the development of all hematopoietic lineages.  Mutation of RUNX is associated with a variety of diseases. The RUNX transcription factor family consists of Runx1, Runx2, and Runx3. The RUNX protein participates in the formation of the adaptive immune system by regulating the development and differentiation of CD4⁺ and CD8⁺ T cells. This article mainly reviews the regulatory mechanisms of RUNX family members in T cell development.

The establishment of immunotherapy is a major breakthrough in the field of tumor therapy which has changed its landscape. Although immunotherapy is effective in some tumor types, the overall response rate is still low. Therefore, the development of new immunotherapy drugs and treatment strategies is needed. Metabolic reprogramming is a main characteristic of tumors, and the complexity of immuno-metabolism in tumor microenvironment is probably an important factor affecting the efficacy of tumor immunotherapy. Recent studies have proved that targeting immuno-metabolism may relieve immunosuppression, enhance anti-tumor immunity, improve the efficacy of current tumor immunotherapy, and even overcome drug resistance. This article reviews the latest progress in tumor immuno-metabolism-targeted therapies, including targeting glucose metabolism, amino acid metabolism, nucleotide metabolism, and lipid metabolism. This review will provide ideas for developing new targets for immuno-metabolism-targeted therapies.

Inflammation is a pathological process dominated by the defensive response to the stimulation of various damage factors in living tissues with the vascular system. Wild-type p53-induced phosphatase 1 (Wip1) is a PP2C family serine/threonine phosphatase encoded by protein phosphatase, Mg²⁺/Mn²⁺ dependent 1D (PPM1D) gene. Wip1 regulates DNA damage repair and the proliferation, senescence, apoptosis, and autophagy of inflammatory cells through regulation of important signaling molecules including dephosphorylation of p38 MAPK, p53 and ataxia telangiectasia-mutated (ATM) protein. Increasing studies have confirmed that Wip1 plays a key role in regulating many types of inflammatory cells. This review summarizes the structural characteristics of Wip1, the relationship between Wip1 and inflammatory cells, and the role of Wip1 in inflammatory diseases.

Sialoadhesin, also known as CD169, is an adhesion and endocytic receptor of macrophages that can recognize sialic acid. CD169 is a highly conservative molecule in evolution. Under physiological conditions, CD169 is expressed on the surface of macrophage subpopulations in secondary lymphoid tissues. Several studies have demonstrated that CD169⁺ macrophages can phagocytize pathogens by interacting with α2,3- and α2,6-sialic proteins, and can also coordinate with DC to cross-present antigens to T cells. Moreover, CD169 can exert an immunosuppression role by inhibiting the expression of type Ⅰ IFN in macrophages. Recently, the roles of CD169⁺ macrophages in various pathological conditions have been reported. It has been shown that when erythropoiesis is under stress, CD169⁺ macrophages can bind to CD43 of erythroblast and affect erythroblast differentiation. In addition, CD169 has been reported to play a dual role during pathogen infection or tumor progression. This review will focus on the advance progress of CD169 and the function of CD169⁺ macrophage, as well as its role in various diseases including virus infection, tumor development, and hematological diseases.

B cells are the major component in the tumor microenvironment and play key roles in tumor immunity. Previous studies have suggested that B cells promote tumor progression via secreting immune-inhibitory cytokines or activating the complement system through  B cell-secreted antibodies. However, recent studies have revealed an important role of B cells in anti-tumor immune responses. This review summarizes the multiple functions of B cells in tumor immunity and discusses the underlying mechanisms and the effects on patients prognosis. 

Autophagy is a process of degradation of cellular contents that occurs in various types of cells in the human body. Dysregulation of autophagy correlates with many human diseases. Innate immune cells are a crucial line of defense in anti-infection immunity. They eliminate pathogenic microorganisms through direct phagocytosis and releasing of bactericidal substances or they may stimulate adaptive immunity through antigen presentation. Autophagy plays a vital role in the anti-infection immunity of innate immune cells. This review focuses on the regulation of autophagy on the anti-infection immunity of innate immune cells including macrophages, neutrophils, and dendritic cells.

The suitable intracellular environment is required for the long-term colonization and survival of intracellular bacteria within host cells. The exact mechanisms of infection and proliferation of most intracellular bacteria in host cells remain unclear. Recent studies have shown that non-coding RNA (ncRNA) could mediate the interaction between pathogens and host cells. The infection of intracellular bacteria induces differential expression of multiple ncRNAs in the nucleus and cytoplasm of host cells, which regulates host growth and metabolism to promote infection and proliferation of the pathogens. In this paper, we briefly review the research progress of the effects of ncRNA in host cells on pathogen proliferation during intracellular infection of Mycobacterium tuberculosis (MTB), Salmonella typhimurium, Chlamydia, Brucella and Listeria monocytogenes (LM) which will provide novel insights in the pathogenesis and clinical treatment of intracellular bacteria.

The tumor microenvironment (TME) has been widely studied in a variety of cancers such as head and neck squamous cell carcinoma (HNSCC).  The TME is of important prognostic significance for tumors and directly guides tumor treatment strategies.  This review discusses the interaction between tumor cells and various components of the HNSCC microenvironment, including immune cells such as neutrophils, macrophages, and T cells/immune checkpoints PD-1/PD-L1. 

Medulloblastoma (MB) is the most common pediatric brain malignancy, with a 5-year overall survival (OS) rate of around 70%. In recent years, the role of the tumor microenvironment on tumor growth has attracted extensive attention. The interaction between tumor cells and other cells in the tumor microenvironment including tumor-associated macrophages (TAM), T cells, NK cells, B cells, and tumor-associated astrocytes (TAA) plays an important role in the onset and progression of MB. Understanding the tumor immune microenvironment of this tumor, especially the relationship between tumor and immune cells, is crucial for the effective development of immune-based therapeutic strategies for MB. This review summarizes the latest research progress on the tumor microenvironment and immunotherapy of MB.

This work aims to develop new treatments for CD3⁺ T cell malignancies. For this purpose, the CD3-targeting monoclonal antibody orthoclone OKT3 (OKT3) was conjugated to the cytotoxic drug monomethyl auristatin E (MMAE) through protease cleavable valine-citrulline (vc) linker to generate an antibody-drug conjugate OKT3-vcMMAE. The molecular weight of OKT3-vcMMAE was verified by SDS-PAGE, and the binding ability to CD3⁺ tumor T cell line was verified by flow cytometry. The in vitro cytotoxic activity of OKT3-vcMMAE was verified by CCK-8, and its capacity to stimulate T cells to release cytokines was tested by the cytometric bead array (CBA). To test the in vivo antitumor efficacy, mice inoculated with T-cell tumor cell lines were treated with OKT3-vcMMAE and tumor burden was measured by bioluminescence imaging. The results showed that OKT3 and OKT3-vcMMAE had a similar affinity to Jurkat cells, with half maximal effective concentration (EC50) of 0.36 and 0.34 μg/mL, respectively. In vitro antitumor experiments revealed that compared to that of the OKT3 group, the viabilities of Jurkat cells in the 1, 10, and 50 μg/mL of OKT3-vcMMAE-treatment groups were significantly decreased (P<0.001). Compared to that of the OKT3 group, the viabilities of HuT78 cells with 10 and 50 μg/mL of OKT3-vcMMAE treatment were significantly decreased (P<0.01). IFN-γ production of primary T cells upon 10 μg/mL of OKT3-vcMMAE treatment was significantly decreased compared to cells treated with OKT3 (P<0.01). In addition, in vivo antitumor experiments showed that compared to that of the PBS control group, the tumor burden of mice in the OKT3-vcMMAE group was significantly reduced on day 13 (P<0.01). This study suggests that the antibody-drug conjugate OKT3-vcMMAE may be a potential treatment for CD3⁺ T cell malignancies, thus providing new insights for the development of anti-T-cell-malignancy drugs.

Neutrophil extracellular trap (NET) discovered seventeen years ago has an essential role in anti-infection immunity. NETs are extracellular DNA fibers containing histones and cytoplasmic granular proteins. They were believed to form a natural immune barrier against pathogens invasion by trapping pathogens, degrading bacterial virulence factors, and killing bacteria. NETs also have effects against other pathogens including fungi, viruses, and parasites. However, the over-formation of NET can lead to a variety of diseases, and NET-associated proteins may also damage tissue. This review concentrates on the role of NET in defending pathogen infections, the immune escape of pathogens from NET, and the dual functions of NET.

Receptor for advanced glycation end products (RAGE), a type of membrane protein, is a member of the immunoglobulin superfamily. Over the past ten years, hundreds of papers have described the correlation between RAGE and the pathophysiological status and prognosis of lung diseases including severe pneumonia, asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung carcinoma. However, many findings were inconsistent. This review summarizes the origin and biological function of RAGE. It also discusses the acting mechanism of RAGE in lung diseases and the therapeutic effect of traditional Chinese medicine via RAGE regulation, aiming to provide new ideas and strategies for improving related lung diseases.

Since the interaction between intestinal microbes and the immune system  was discovered, the key role of intestinal flora in rheumatic diseases has been recognized and studied by ever-increasing scholars, and has become a research hotspot. Intestinal flora not only participate in the organism nutrient absorption, material metabolism and energy conversion, but also play an important role in the development and maturation of the immune system, the differentiation of immune cells and the regulation of immune mediators. The pathogenesis of ankylosing spondylitis (AS) is not fully understood but it is may be a genetic disease related to the HLA-B27. The inflammation of the sacroiliac joint and spinal attachment point caused by autoimmune abnormalities is the main pathological feature. The latest researches have shown that the intestinal flora are closely related to  HLA-B27, the development and regulation of the immune system, IL-23/Th17 axis and other factors that affect the pathogenesis of AS. Therefore, this article reviews the relationship between the intestinal flora, the immune system and AS, and provides a new perspective for the research and clinical application on rheumatic immune diseases. 

NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome is a protein complex that stimulates the activation of caspase and the maturation of IL-1β, and promotes the pathogenesis and development of various inflammations. The occurrence of periodontitis (PD) is related to the dysbacteriosis of periodontal tissue. NLRP3 inflammasomes are involved in the activation of neutrophil, macrophage, osteoclast (OC), and human periodontal ligament fibroblast (HPLF). This review summarizes the effects of NLRP3 inflammasome in the related immune and stromal cells on PD, and outlines new ideas for PD treatment targeting NLRP3 inflammasome.

Corona virus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global health emergency. Adaptive immune response plays a critical role in clearing virus-infected host cells, mainly relying on T cells. The structure of the T cell receptor (TCR) determines the specificity of viral antigen cluster recognition, and the characteristics of the TCR complementarity determining region 3 (CDR3) repertoire of infected individuals have indications  for the occurrence and development of COVID-19 disease. Additionally, human leukocyte antigen (HLA) gene is the main factor responsible for individual varieties in immune responses to antigens and plays an important role in human immune responses. This review focuses on the research progress and overview of the relationships of TCR CDR3 repertoire characteristics and of the composition of host HLA alleles with COVID-19.

This study aims to improve the accuracy of multi-microsphere flow immunofluorescence assay in the clinical detection of cytokines. To this end, peripheral blood samples from patients were collected, and the effects of serum, plasma, different storage conditions, and interfering substances on the results of 12 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, IFN-γ, IFN-α, and TNF-α) were analyzed. The results showed that the levels of IL-6 and IL-8 in the serum sample were significantly higher than those in the plasma sample (P<0.05), while the levels of the other cytokines including IFN-α, TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-10, IL-12p70, and IL-17 showed no difference between serum and plasma (P>0.05). The levels of some cytokines changed slightly when EDTA-K2 was used as anticoagulation in whole blood samples stored at 4 ℃ for 24 h. However, the cytokines levels in plasma decreased significantly after being stored at 4 ℃ for 48 h (P<0.05). The detection signal and analysis results of abnormal samples (missing microspheres or abnormally enhanced fluorescence signal) were returned to normal after pretreatment with mouse immunoglobulin. The study indicates that the cytokine levels in EDTA-K2 anticoagulant plasma samples or samples stored at 4 ℃ within 24 h are more stable than those in whole blood samples. In addition, pretreatment with mouse immunoglobulin is an effective method to solve the loss of microspheres or abnormal fluorescence signals of microspheres. 

Immunotherapy has become one of the main modalities for tumor treatment. CTLA-4 and PD-1 are the two main players in tumor immune escape. However, the low response rate of PD-1 and CTLA-4 treatments is the main challenge facing tumor immunotherapy at present. Lymphocyte activation gene 3 (LAG-3), a new-generation inhibitory immune checkpoint, plays an important regulatory role in the human immune system. LAG-3 is highly expressed on various types of TIL and mediates tumor immune escape through multiple mechanisms. LAG-3 can also be co-expressed with PD-1 in TIL. Combined blockade of LAG-3 and PD-1 synergistically inhibits immune escape, increases antitumor response, and enhances T cell proliferation. It has become one of the most promising immunotherapies to improve the current deficiencies in tumor immunotherapy. Therefore, it is of great significance to deeply understand the biological characteristics of LAG-3 and further explore its mechanism of action. In addition, the structure and function of LAG-3 as well as its research progress in tumor immunity are reviewed.

There are two forms of thyroid hormone (TH): 3, 5, 3'-triiodothyronine (T3) and 3, 5, 3', 5'-tetraiodothyronine (T4, or termed thyroxine). They act on almost all tissues of the body, with a wide range of biological processes including metabolism, growth, and development. Recent studies have brought attention to their regulation on innate immune cells. Thyroxine has been shown to affect the M1 and M2 states of macrophages. In addition, macrophages express type 2 deiodinase (D2), which can regulate different molecular forms of intracellular TH. The abnormal thyroid function also affects the biological activity of macrophages such as their anti-inflammatory activity. In addition, hypothyroidism aggravates atherosclerosis. Although there is no sufficient evidence to prove the clinical correlation between thyroid hormones and macrophages, thyroid hormone level may be used as a factor to predict clinical susceptibility to infections, tumors, and autoimmune diseases. 

 Neutrophils are one of the most important effector cells in innate immunity and the defense at the frontline against invading pathogens. With the continuous advances, people have realized that neutrophils not only participate in the inflammatory response and tissue damage repair, tumor-associated neutrophils also act as anti- or pro-tumorigenic factors depending on specific tumor microenvironment (TME) status. Neutrophils with different functions may have different phenotypes and also some plasticity. This review begins with the biological properties of neutrophils, and then summarizes the diverse phenotypes of neutrophils with different functions in the TME, the possible mechanisms of immunosuppressive neutrophils regulating tumor immunity, and the clinical application of neutrophils in cancer research.

This study aims to investigate the expression of PD-L1 in human colorectal cancer (CRC) and its correlation with clinicopathological characteristics. PD-L1 expression was measured by immunohistochemistry of CRC patients and analyzed to reveal its relationship with histological tumor grade and metastasis. PD-L1 expressions in CRC tissue and para-cancerous tissue were measured by ELISA. The results showed that PD-L1 expression was significantly correlated with histological tumor grade. PD-L1 expression increased with the decreasing of tumor differentiation levels from high to low (P<0.01). However, there was no apparent correlation between PD-L1 expression and metastasis condition (P>0.05). The expression of PD-L1 in CRC tissue was significantly higher than that in para-cancerous tissue (P<0.001). The study suggests that PD-L1 expression is higher in CRC tissue, compared to that in para-cancerous tissue, and PD-L1 expression is significantly associated with histological tumor grade, making it a potential indicator to assess the clinical prognosis of CRC patients. 

To investigate the effect and mechanism of paeoniflorin (PF) on human bronchial epithelial cells (BEAS-2B), THP-1 cells were induced to differentiate into macrophages by phorbol 12-myristate 13-acetate, and the toxicity of PF to THP-1 macrophages was detected by CCK-8 assay. THP-1 macrophages were cultured with 1 μg/mL LPS to induce inflammation, and treated with 1, 10, and 30 μmol/L PF for 24, 48, and 72 h, respectively. Cell viability was detected by CCK-8 assay, and the optimal concentration and treating time of PF were determined. BEAS-2B cells were inoculated in the upper chamber of Transwell and THP-1 macrophages were inoculated in the lower chamber of Transwell. THP-1 macrophages were divided into 4 groups: control group, LPS group, PF group, and LPS+PF group. The survival rate of BEAS-2B cells was detected by CCK-8 assay, the apoptosis rate of BEAS-2B cells was detected by FACS, the levels of inflammatory cytokines IFN-γ, IL-4, IL-17C, and IL-10 were detected by ELISA, and the expression levels of CD63, CD9, and apoptosis-linked gene 2-interaction protein X (Alix)  were detected by Western blotting. The expressions of M1 and M2 markers CD80 and CD206 in THP-1 macro-phages were detected by FACS. The results showed that the optimal concentration and treating time of PF were 10 μmol/L and 48 h. Compared to those in the control group, the cell survival rate, IL-4 and IL-10 levels and the proportion of M2-type macrophages in the LPS group were significantly decreased (P<0.01). On the other hand, the apoptosis rate, IFN-γ and IL-17C levels, CD63, CD9, Alix protein expression levels and the proportion of M1-type macrophages were significantly increased (P<0.01). Compared to those in the LPS group, the cell survival rate, IL-4 and IL-10 levels and the proportion of M2-type macrophages in the LPS+PF group were significantly increased (P<0.01), while the apoptosis rate, IFN-γ and IL-17C levels, CD63, CD9, Alix protein expression levels and the proportion of M1-type macrophages were significantly decreased (P<0.01). These results suggest that PF can improve the survival rate of BEAS-2B cells, reduce apoptosis, and inhibit exosome secretion and inflammatory response. The underlying mechanism may be related to PF induced M2-type polarization of macrophages.

The aim of this study is to investigate the immuno-modulatory effect of IL-17A preconditioned (ameliorated) adipose-derived mesenchymal stem cells (ADSCs）on peripheral blood lymphocytes and to explore the underlying mechanism.  Subcutaneous adipose tissue was collected from four abdominal surgery patients consulting Tianjin People's Hospital, along with the peripheral blood. ADSCs  were isolated, cultured and identified. Next, ADSCs were divided into two groups preconditioned with or without IL-17A (named ADSC-17 group and ADSC group, respectively), which were co-cultured with phytohemagglutinin (PHA)+IL-2-stimulated lymphocytes. The proliferation inhibitory rate of activated lymphocytes was analyzed by MTT assay. The percentage of CD4⁺CD25⁺ T lymphocytes was detected by FACS. ELISA was performed to detect the TGF-β1 level in culture supernatants. The results revealed that after in vitro culturing, both ADSC and ADSC-17 groups strongly expressed cluster of differentiation (CD)90, CD105, and CD73 as well as displayed osteogenic and adipogenic potentials. The ADSC-17 group showed significantly enhanced proliferation inhibitory rate of activated lymphocytes in a dose-dependent manner compared to that of the ADSC group (all with P＜0.01). The percentage of CD4⁺CD25⁺ T lymphocytes and the secretion of TGF-β1 in ADSC-17 group were significantly increased (both P＜0.05) compared to those of the ADSC group. Altogether, the preconditioning of ADSCs by IL-17A can augment the capacity of ADSC to inhibit lymphocyte proliferation and to induce CD4⁺CD25⁺ T lymphocyte  differentiation so as to become an effective strategy for inducing lymphocytes hypo-responsiveness.

In this study, a type of fluorescence immuno-chromatography reagent card that may be applied for the quick quantitative detection of IL-6 was developed. A recombinant human IL-6 protein was expressed in E. coli as a standard for the IL-6 testing  card. First, the human IL-6 gene was cloned to the expression vector pET30a after codon optimization, which was subsequently transformed into E. coli BL21 competent cells for inducible expression. By isopropylthio-β-D-galactoside (IPTG) induction, the soluble form of IL-6 protein was obtained. After  Ni2+ column affinity chromatography purification and ultrafiltration, the IL-6 protein standard sample was acquired. The fluorescence immuno-chromatography reagent card was prepared by time-resolved fluorescent microspheres, based on the fluorescence immuno-chromatography technology and sandwich ELISA. By property evaluation, the blank limit was 5.2 pg/mL. The coefficient of variation was between 7.34% to 11.11%, exhibiting good repeatability. The recovery rate was between 96.3% and 107.2%. The reagent card showed good stability after six weeks storage at 37 ℃. There was no cross-reaction with common competitors, with the reference value ranging from 0 to 9.0 pg/mL. The outcome of our method on the clinical samples testing was comparable to that of the electrochemi-luminescence immunoassay (ECLIA) (r = 0.965). In conclusion, the recombinant IL-6 protein prepared in this study is of high purity and concentration, which is qualified as kit testing standard. And the developed reagent card is convenient to use and could meet the needs of clinical applications.

Age-associated B cell (ABC) is a new B cell subset discovered in recent years, which accumulates in spleen with age. This type of cell has unique cellular phenotypes and transcriptional features. ABC highly expresses myeloid marker CD11c and transcription factor T-bet, and differentiates and proliferates upon the stimulation of Th1 cytokines and TLR7 and/or TLR9. It can differentiate into plasma cells to produce antibodies, secrete cytokines, and present antigens. ABC plays an important role in immune aging and autoimmune disease. This review aims to introduce the phenotypic characteristics, origin, anatomical distribution, differentiation regulation mechanism, and function of ABC, clarify its role in immune aging and autoimmune diseases, and provide a new target for clinical treatment.

CD8⁺ Treg can be divided into a diversity of cell subsets with distinct phenotypes, whose characteristic markers have great heterogeneity due to differences in cell origins, induction methods, physiological or pathological circumstances, and negative regulation mechanisms. This paper summarizes the latest research on the heterogeneity and immunobiological properties of CD8⁺ Treg, including the origin, lineage differentiation, potential transcription factors, and the signaling pathways underlying cell differentiation and induction, thus providing a comprehensive understanding of CD8⁺ Treg.

As a type of APC, macrophages play an important role in both innate and adaptive immune responses, involving in phagocytosis, tissue remodeling and repair, angiogenesis, and immune tolerance. During pregnancy, macrophages are broadly located at the maternal-fetal interface and own diverse functions and plasticity. Preeclampsia (PE) is a serious complication of pregnancy whose pathogenesis is yet to be elucidated. In recent years, the role of macrophages at the maternal-fetal interface in PE has attracted increasing attention. Starting from the classification and regulation of maternal-fetal interface macrophages, this review focuses on their role in various pathologic processes of PE, including insufficient trophoblastic invasion, uterus spiral arterial remodeling disorder, the immune imbalance of maternal-fetal interface, vasoendothelial damage and metabolic   reprogramming.

Vedolizumab is a humanized anti-integrin α4β7 monoclonal antibody believed to exhibit high intestinal specificity. Its impact on the immune system of patients with inflammatory bowel disease (IBD) is reported to be mostly restricted to the intestine. In a humanized mouse model, vedolizumab blocks T-cell trafficking to inflamed intestinal tissue. Therefore, preventing the transport of T cells to the gut is thought to be the main mechanism of vedolizumab in reducing intestinal inflammation. However, with the wide application of vedolizumab, its effects on systems other than the gut have been reported. In addition, its target cells are found not limited to T cells. Vedolizumab also acts on innate immune cells as well as B cells in the gut of IBD patients. Besides, vedolizumab may also be used to treat extra-intestinal manifestation (EIM) accompanied with enteral disease activity, such as peripheral arthritis and erythema nodosum. This review summarizes the effects of vedolizumab on different systems in IBD patients to help fully understand the mechanism of action of vedolizumab.

To investigate the mechanism by which salidroside improves keloid on regulating JAG1/Notch3 signaling pathway through miR-26a-5p, 10 keloid patients diagnosed by histopathology in Wuhan Hospital of Traditional Chinese Medicine were enrolled as the research objects from October 2019 to January 2021. The keloid tissues removed by surgery were used in the keloid group, and the adjacent healthy skin tissues were used in the normal group. Primary keloid fibroblasts were isolated and cultured, and the cells of generation 4~8 were divided into 8 groups: control group (normal culture), salidroside low-dose group (10 μmol/L salidroside), salidroside medium-dose group (20 μmol/L salidroside), salidroside high-dose group (40 μmol/L salidroside), miR-NC group (40 μmol/L salidroside+miR-NC), miR-26a-5p inhibitor group (40 μmol/L salidroside+miR-26a-5p inhibitor), sh-RNA group (40 μmol/L salidroside+miR-26a-5p inhibitor+sh-RNA) and sh-JAG1 group (40 μmol/L salidroside+miR-26a-5p inhibitor+sh-JAG1). Cells in each group were treated with salidroside for 24 h after transfection or directly treated with the corresponding dosage of salidroside for 24 h. The relative mRNA expressions of miR-26a-5p and JAG1  in tissues and cells were quantified using qRT-PCR. Cell proliferating viability was measured by the MTT assay and cell cloning capacity was detected using the plate cloning method. Cell apoptosis was detected by FACS and cell migration and invasion were assessed by Transwell method. Luciferase reporter system was utilized to examine the targeting interaction between miR-26a-5p and JAG1. Western blotting was used to detect the expressions of tissue hyperplasia-related proteins. The results showed that, compared to that of the normal group, the expression of miR-26a-5p in keloid group was significantly decreased (P＜0.05), while the JAG1  expression significantly increased (P＜0.05). Compared to the 0 μmol/L salidroside group, 10, 20, 40, 80, and 160 μmol/L salidroside treatment inhibited the survival rate of keloid fibroblasts in a concentration-dependent manner (all with P＜0.05). To ensure both the survival of keloid fibroblasts and the effect of salidroside, subsequent experiments were conducted with salidroside concentrations of 10, 20, and 40 μmol/L (It was proved that miR-26a-5p combines to JAG1). In the three salidroside groups, compared to those of the control group, the expression of miR-26a-5p and the apoptosis rate increased dependently, while the expression of JAG1, the numbers of cell clones, cell migrations, and invasions, and the expression of α-SMA, collagen Ⅰ, collagen Ⅲ, JAG1, and Notch3 proteins decreased significantly (all with P＜0.05). Compared to those of the salidroside high-dose group and the miR-NC group, the expression of miR-26a-5p and the cell apoptosis rate in the miR-26a-5p inhibitor group reduced significantly, while the expression of JAG1, the numbers of cell clones, migration and invasion, and the expression of α-SMA, collagen Ⅰ, collagen Ⅲ, JAG1 and Notch3 proteins increased significantly (all with P＜0.05). Inhibition of JAG1  expression suppressed the effect of miR-26a-5p inhibitor on promoting cell proliferation, migration and invasion, and on inhibiting cell apoptosis. In conclusion, the expression of miR-26a-5p is down-regulated and JAG1  is up-regulated in keloid tissue, salidroside can inhibit the JAG1/Notch3 signaling pathway and the proliferation, migration and invasion of keloid fibroblasts, while promoting cell apoptosis, which in turn improves keloid by up-regulating the expression of miR-26a-5p.

More and more studies have shown that the occurrence of atherosclerosis is closely related to pyroptosis, especially gasdermin D（GSDMD）-mediated pyroptosis. In atherosclerosis, inflammatory cells such as macrophages, vascular endothelial cells, and vascular smooth muscle cells undergo pyroptosis, leading to plaque rupture and thrombosis, and finally to acute coronary syndrome. In the development of atherosclerosis, arterial wall endothelial injury and lipid deposition are the main initiating factors, which activate Caspase-1 and Caspase-11/4/5, respectively, and in turn cause the cleavage of the GSDMD protein and mediate classical and non-classical cell pyroptosis. The N-terminus of the GSDMD protein migrates to the cell membrane and oligomerizes to form pores through which the inflammatory factors IL-1β and IL-18 are released into the interstitium. The release of inflammatory factors further promotes the death of intravascular cells, after which their contents, cytokines, and proteases enter the extracellular matrix, aggravating the local inflammatory response, leading to atherosclerotic plaque rupture and cardiovascular disease. Based on the above mechanism, the development of drugs that directly target GSDMD and signal molecules in the pyroptosis signaling pathway induced by GSDMD, such as inflammasomes, Caspase-1, IL-1β, and IL-18, provides a theoretical basis and new ideas for the treatment of atherosclerosis.

To investigate the role and mechanism of long non-coding RNA (LncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) in immune escape of non-small cell lung cancer (NSCLC), the tumor tissues and adjacent normal tissues of 96 NSCLC patients were collected in this study.  qRT-PCR was used to detect the expression of NEAT1 in NSCLC tumors and normal tissues, and its correlation with the clinicopathologic feature of NSCLC patients was analyzed.  In addition, qRT-PCR was used to detect the expression of NEAT1, miR-128-3p, heterogeneous nuclear ribonucleoprotein L (HNRNPL), and PD-L1 mRNAs in bronchial epithelial cells 16HBE and NSCLC cell lines. NEAT1 interference plasmid (si-NEAT1), miR-128-3p inhibitor, and controls (si-NC and inhibitor-NC) were transfected into A549 cells and divided into control group, si-NC group, si-NEAT1 group, si-NEAT1+anti-NC group, and si-NEAT1+anti-miR-128-3p group. The mRNA and protein expressions of HNRNPL and PD-L1 were measured and the regulatory mechanisms of NEAT1, miR-128-3p, and HNRNPL were verified by RNA pull-down experiment. A549 cells were co-cultured with CD8⁺ T cells to verify the role of NEAT1 knockdown in NSCLC immune escape. The levels of PD-L1 and IFN-γ were detected by ELISA. The results showed that NEAT1 was highly expressed in NSCLC tumor tissues, and it significantly correlated with NSCLC tumor size, TNM stage, and lymph node metastasis (P<0.05). In NSCLC tumor cells, NEAT1, HNRNPL, and PD-L1 were significantly overexpressed, while miR-128-3p was significantly underexpressed (all P<0.05). Knockdown of NEAT1 up-regulated miR-128-3p while inhibiting HNRNPL and PD-L1 expressions, which in turn significantly reduced NSCLC cell viability and induced NSCLC cell apoptosis (all P<0.05). NEAT1 targeted and bound miR-128-3p in NSCLC cells. In the co-culture system, knocking down NEAT1 in A549 cells could activate CD8⁺ T cells, inhibit their apoptosis and reduce the levels of PD-L1 and IFN-γ (all P<0.05). Down-regulation of miR-128-3p increased the expressions of HNRNPL and PD-L1, and attenuated the impact of NEAT1 knockdown on NSCLC cell proliferation, apoptosis, and CD8⁺ T cell activation (all P<0.05). Therefore, NEAT1 may promote PD-L1 expression through the miR-128-3p/HNRNPL axis, thereby leading to immune escape in NSCLC.

Signet ring cell carcinoma (SRCC) is a rare but distinctive pathological subtype of colorectal cancer (CRC) with a mucin-rich phenotype as well as high metastatic rate and poor prognosis. In our large cohort of single-cell RNA sequencing (scRNA-seq) study of CRC, one case of SRCC was serendipitously enrolled. It is currently the first scRNA-seq data of SRCC derived from CRC in the world. Using this batch of scRNA-seq data including the SRCC, we aimed to compare the SRCC case with common adenocarcinoma (AC) in order to elucidate the cellular and molecular mechanisms behind SRCC. The results suggested that goblet-like malignant cells in SRCC contributed to its unique phenotypes. These cells specifically upregulated protein processing and cell adhesion related signaling pathways and overexpressed multiple mucin genes. Epithelial to mesenchymal transition (EMT) was associated with CRC metastasis. SRCC exhibited high level of EMT, in accordance with its high malignancy. However, the EMT related genes in SRCC were different from those of common AC. The potential prognostic role of genes related to EMT was revealed by combining the transcriptomic data and follow-up information of CRC in The Cancer Genome Atlas (TCGA) database. Compared to AC, SRCC had a smaller proportion of lymphocytes and a larger proportion of myeloid cells, and the correlation between epithelial and immune cells was reduced. Collagen and integrins interacted extensively between epithelial cells and stromal cells in CRC. This study is the first to characterize colorectal SRCC at the single cell level which is a powerful complement to the single-cell atlas of CRC, and provides new insights into the therapeutic targets of colorectal SRCC. 

Radiation-induced bystander effect (RIBE) is one of the mechanisms of ionizing radiation-induced biological effects, which may be mediated by a variety of pathways. Exosomes are 30~150 nm diameter bilayer lipid membrane-rounding vesicles actively released by living cells and were widely distributed in body fluids. They carry signal molecules including nucleic acids and proteins to play important roles in inter-cellular communications. Recently, it has been found that exosomes can participate in the formation of RIBE and mediate the occurrence of immune responses due to ionizing radiation. The immune system is one of the main targets for ionizing radiation, and the damage of the immune system is also the main cause of the most common diseases and  life quality decline of patients suffering from nuclear accidents. Therefore, it has persisted a hotspot in the field of radiation biology to comprehensively reveal the mechanism of RIBE in the ionizing radiation-induced immune effect. This review discusses the role of RIBE in the ionizing radiation-induced immune effect  from the perspective of exosome and summarizes the biological mechanisms of exosome in this process in order to form a scientific basis for further study of the mechanism of radiation biological effects and for the exploration of radiation injury prevention and treatment strategies.

Protein kinase CK2 is a highly conserved and ubiquitous protein kinase which phosphorylates a variety of protein substrates, and is involved in the regulation of several signaling pathways. Abnormal CK2 expression can lead to dysregulation of various signaling pathways, which is closely related to tumorigenesis and progression. This review summarizes the composition, structure and regulatory role of CK2 in important tumor-related signaling pathways and provides foundation to further explore CK2-targeted therapeutic strategies in cancer.

Aging is an inevitable stage in the metabolic process of human body which also affects the immune system, among which the changes of T cells are the most obvious. Mitochondrial dysfunction is one of the important reasons for cellular senescence. Recent studies have shown that viral infection can alter the metabolism of host cells by inducing mitochondrial damage which causes immunosenescence. This review aims to summarize the research progress on the role of virus infection-induced mitochondrial damage in T cell senescence including mitochondrial function, the effect of virus infection on mitochondrial damage, and the relationship between mitochondrial damage and T cell senescence.

Kidney stone is a disease of high incidence and recurrence rate and has become an obstacle in urology. Recent studies have demonstrated the role macrophages play in the development of calcium oxalate nephrolithiasis. Macrophages regulate the occurrence and development of calcium oxalate nephrolithiasis via various mechanisms, such as polarization into different subtypes, secretion of cytokines, crystals phagocytosis, and activation of signal transduction pathways. This review discusses the research progress on the mechanism of macrophages in calcium oxalate nephrolithiasis.

Inflammatory diseases are a series of acute or chronic diseases caused by inflammatory response to stimulation, which may seriously harm human health. Traditional Chinese medicine, which has multiple targets in immunomodulatory processes, plays a key role in the treatment of various inflammatory diseases. Corilagin is one of the major bioactive compounds in many medicinal plants. It has a variety of biological and pharmacological activities, including anti-oxidation, anti-inflammatory, liver protection, anti-virus, anti-hypertension, anti-infection, and anti-tumor. It has attracted extensive attention in recent years. However, there is a lack of systematic understanding of the role corilagin plays in inflammatory diseases. To better develop and utilize the medicinal plant resources in China, this review summarizes the role and related mechanism of corilagin in various inflammatory diseases. It will provide references for both follow-up basic research and clinical application of corilagin.