Single-Cell Sequencing Informs That Mesenchymal Stem Cell Alleviates Renal Injury Through Regulating Kidney Regional Immunity in Lupus Nephritis.

Lupus nephritis (LN) is the common complication of systemic lupus erythematosus. The pathogenesis of LN kidney injury is unclear. In addition to systemic (extrarenal) immune cells, local (intrarenal) immune cells residing in "kidney regional immunity" are momentous in LN. Mesenchymal stem cell (MSC) therapy is effective for LN. However, mechanisms of MSC therapy remains unclear. In this study, we first systematically investigated the effects of MSC on immune cells in kidney regional immunity in LN using single-cell sequencing. We found that MSC reduced proinflammatory central memory CD4+ T cells, cytotoxic tissue-resident memory CD8+ T cells and exhausted CD8+ T cells, increased anti-inflammatory Naive/Effector CD8+ T cells and type 1 regulatory T cells; reduced infiltrating proinflammatory Ly6c hi/inter/lo era2+ macrophages, increased anti-inflammatory resident macrophage and Ly6c lo ear2- macrophage; and reduced long-lived plasma cells and proinflammatory neutrophils and dendritic cells. This study laid a foundation for clinical applications of MSC.

Longitudinal Modulation of Loco-Regional Immunity in Ovarian Cancer Patients Receiving Intraperitoneal Chemotherapy.

The immune tumor microenvironment (TME) of epithelial ovarian cancer (EOC) carries both effector and suppressive functions. To define immune correlates of chemotherapy-induced tumor involution, we performed longitudinal evaluation of biomarker expression on serial biological specimens collected during intraperitoneal (IP) platinum-based chemotherapy. Serial biological samples were collected at several time points during IP chemotherapy. RNA from IP fluid cells and tumor tissue was analyzed via NanoString. Meso Scale Discovery (MSD) multiplex assay and ELISA for MUC1 antibodies were performed on plasma and IP fluid. Differentially expressed genes in IP fluid demonstrate an upregulation of B cell function and activation of Th2 immune response along with dampening of Th1 immunity during chemotherapy. MSD analysis of IP fluid and gene expression analysis of tumor tissue revealed activation of Th2 immunity and the complement system. Anti-MUC1 antibodies were detected in IP fluid samples. IP fluid analysis in a secondary cohort also identified chemotherapy-induced B cell function genes. This study shows that serial IP fluid sampling is an effective method to capture changes in the immune TME during chemotherapy and reveals treatment induced changes in B cell function and Th2 immunity.

Inflammation Self-Limiting Electrospun Fibrous Tape via Regional Immunity for Deep Soft Tissue Repair.

Overexpression of inflammatory cytokines and chemokines occurs at deep soft tissue injury sites impeding the inflammation self-limiting and impairing the tissue remodeling process. Inspired by the electrostatically extracellular matrix (ECM) binding property of the inflammatory signals, an inflammation self-limiting fibrous tape is designed by covalently modifying the thermosensitive methacrylated gelatin (GelMA) and negatively charged methacrylated heparin (HepMA) hydrogel mixture with proper ratio onto the electrospun fibrous membrane by mild alkali hydrolysis and carboxyl-amino condensation reaction to restore inflammation self-limiting and promote tissue repair via regional immunity regulation. While the GelMA guarantees cell compatibility, the negatively charged HepMA successfully adsorbs the inflammatory cytokines and chemokines by electrostatic interactions and inhibits immune cell migration in vitro. Furthermore, in vivo inflammation self-limiting and regional immunity regulation efficacy is evaluated in a rat abdominal hernia model. Reduced local inflammatory cytokines and chemokines in the early stage and increased angiogenesis and ECM remodeling in the later phase confirm that the tape is an approach to maintain an optimal regional immune activation level after soft tissue injury. Overall, the reported electrospun fibrous tape will find its way into clinical transformation and solve the challenges of deep soft tissue injury.

Self-Tolerance of Vascular Tissues Is Broken Down by Vascular Dendritic Cells in Response to Systemic Inflammation to Initiate Regional Autoinflammation.

The correlation of infections with vascular autoinflammatory diseases such as vasculitis and atherosclerosis has been long recognized, and progressive inflammation with the formation of tertiary lymphoid organs in arterial adventitia intensively studied, the immunological basis of the nondiseased vasculatures that predispose to subsequent vascular autoimmunity during inflammation, however, is not well characterized. Here, we investigated the vascular immunity in situ of steady-state C57BL/6 mice and found that healthy vascular tissues contained a comprehensive set of immune cells with relatively higher proportion of innate components than lymphoid organs. Notably, a complete set of dendritic cell (DC) subsets was observed with monocyte-derived DCs (moDCs) constituting a major proportion; this is in contrast to moDCs being considered rare in the steady state. Interestingly, these vascular DCs constitutively expressed more suppressive factors with cDC1 for PD-L1 and moDCs for IL-10; this is concordant with the inhibitive phenotype of T cells in normal vascular tissues. The immunotolerant state of the vascular tissues, however, was readily eroded by systemic inflammation, demonstrated by the upregulation of proinflammatory cytokines and enhanced antigen presentation by vascular DCs to activate both cellular and humoral immunity in situ, which ultimately led to vascular destruction. Different vascular DC subsets elicited selective effects: moDCs were potent cytokine producers and B-cell activators, whereas cDCs, particularly, cDC1, were efficient at presenting antigens to stimulate T cells. Together, we unveil regional immunological features of vascular tissues to explain their dual facets under physiological versus pathological conditions for the better understanding and treatment of cardiovascular autoinflammation.

NK Cell Dysfunction and Checkpoint Immunotherapy.

NK cells play important roles in the innate immune responses against tumors. The effector function of NK cells relies on the integration of activating and inhibitory signals. Emerging checkpoint receptors and molecules are being revealed to mediate NK cell dysfunction in the tumor microenvironment. Inhibition of some NK cell surface checkpoint receptors has displayed the potential to reverse NK cell dysfunction in tumors, and to boost anti-tumor immunity, both in clinical trials (anti-KIR and anti-NKG2A), and in preclinical studies (e.g., anti-TIGIT, and anti-CD96). To fully exploit the potential of NK-based checkpoint immunotherapy, more understanding of the regional features of NK cells in the tumor microenvironment is required. This will provide valuable information regarding the dynamic nature of NK cell immune response against tumors, as well as novel checkpoints or pathways to be targeted. In this Review, we discuss recent advances in the understanding of NK cell dysfunction in tumors, as well as emerging strategies of NK-based checkpoint immunotherapy for tumors.

[Expression of B7 Family Co-inhibitory Molecules in the Establishment of Pulmonary Regional Immunity].

OBJECTIVE: To identify the temporal-spatial expression of B7 family co-inhibitory molecules during lung development, and to explore the roles of B7 family co-inhibitory molecules in the developmental process of pulmonary regional immunity. METHODS: The expression of B7 family co-inhibitory molecules (B7-1, B7-2, B7-H1, B7-DC) in different developmental stages of Rhesus monkey lungs were normalized and calculated by the reads per kilo-base of transcript per million mapped reads (RPKM) method. Immunohistochemical staining was performed to identify the localization and the protein of B7 family co-inhibitory molecules in different developmental phase (canalicular stage, cystic stage, alveolar stage) in mouse. RESULTS: The expression of B7 family co-inhibitory molecules in rhesus monkey were increased during the prenatal period (cystic stage, alveolar stage), the expressions of B7-2 and B7-H1 mRNA were significantly increased in alveolar stage (P<0.05). The results of immuno-histochemistry indicated that B7 family co-inhibitory molecules were mainly expressed in airway epithelial cells, and their protein levels were increased during the prenatal period. The expressions of B7-2, B7-H1 and B7-DC were significantly increased from canalicular stage (P<0.05). The protein of B7-2 was higher in airway than that in bronchus (P<0.05). CONCLUSIONS: B7 family co-inhibitory molecules are mainly expressed in airway epithelial cells, and the expressions are increased during the prenatal period, which suggests that B7 family co-inhibitory molecules are involved possibly in the development of pulmonary regional immunity.

Immune cell trafficking and dynamic immunity / 中国免疫学杂志

Immune cell trafficking is a fundamental feature and common phenomenon in immunity. The dynamic trafficking of immune cells and interactions among immune cells and microenvironmental stromal cells underlie various immune events and play important roles for immune development and function. In this review,the major and representative progresses in this field in recent years were summarized and discussed.

Advancement in regional immunity and its clinical implication.

Organs in our body have formed their own unique immune surveillance system that is finely tuned by in situ milieu. Sequestrated tissue-resident immune cells differ from their counterparts in circulation and participate in tissue physiological activities and the maintenance of local homeostasis. Dysregulation of regional immunity leads to organ-specific inflammatory injuries. Here we review the recent developments in the field of tissue-resident immune cells and organ-specific regional immunity, and discuss their clinical implication.

Guards at the gate: physiological and pathological roles of tissue-resident innate lymphoid cells in the lung.

The lung is an important open organ and the primary site of respiration. Many life-threatening diseases develop in the lung, e.g., pneumonia, asthma, chronic obstructive pulmonary diseases (COPDs), pulmonary fibrosis, and lung cancer. In the lung, innate immunity serves as the frontline in both anti-irritant response and anti-tumor defense and is also critical for mucosal homeostasis; thus, it plays an important role in containing these pulmonary diseases. Innate lymphoid cells (ILCs), characterized by their strict tissue residence and distinct function in the mucosa, are attracting increased attention in innate immunity. Upon sensing the danger signals from damaged epithelium, ILCs activate, proliferate, and release numerous cytokines with specific local functions; they also participate in mucosal immune-surveillance, immune-regulation, and homeostasis. However, when their functions become uncontrolled, ILCs can enhance pathological states and induce diseases. In this review, we discuss the physiological and pathological functions of ILC subsets 1 to 3 in the lung, and how the pathogenic environment affects the function and plasticity of ILCs.

Guards at the gate: physiological and pathological roles of tissue-resident innate lymphoid cells in the lung

The lung is an important open organ and the primary site of respiration. Many life-threatening diseases develop in the lung, e.g., pneumonia, asthma, chronic obstructive pulmonary diseases (COPDs), pulmonary fibrosis, and lung cancer. In the lung, innate immunity serves as the frontline in both anti-irritant response and anti-tumor defense and is also critical for mucosal homeostasis; thus, it plays an important role in containing these pulmonary diseases. Innate lymphoid cells (ILCs), characterized by their strict tissue residence and distinct function in the mucosa, are attracting increased attention in innate immunity. Upon sensing the danger signals from damaged epithelium, ILCs activate, proliferate, and release numerous cytokines with specific local functions; they also participate in mucosal immune-surveillance, immune-regulation, and homeostasis. However, when their functions become uncontrolled, ILCs can enhance pathological states and induce diseases. In this review, we discuss the physiological and pathological functions of ILC subsets 1 to 3 in the lung, and how the pathogenic environment affects the function and plasticity of ILCs.