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The emergence of synthetic biology has opened new avenues in constructing cell-assembly biosystems with specific gene expression and function. The phenomena of cell spreading and detachment during tissue development and cancer metastasis are caused by surface tension, which in turn results from differences in cell-cell adhesion mediated by the dimerization of cadherin expressed on the cell surface. In this study, E- and P-cadherin plasmids were first constructed based on the differential adhesion hypothesis, then they were electroporated into K562 cells and HEK293T cells, respectively, to explore the process of cell migration and assembly regulated by cadherins. Using this approach, some special 3D cell functional components with a phase separation structure were fabricated successfully. Our work will be of potential application in the construction of self-assembling synthetic tissues and organoids.

The surface inhibitory receptor NKG2A forms heterodimers with the invariant CD94 chain and is expressed on a subset of activated CD8 T cells. As antibodies to block NKG2A are currently tested in several efficacy trials for different tumor indications, it is important to characterize the NKG2A + CD8 T cell population in the context of other inhibitory receptors. Here we used a well-controlled culture system to study the kinetics of inhibitory receptor expression. Naïve mouse CD8 T cells were synchronously and repeatedly activated by artificial antigen presenting cells in the presence of the homeostatic cytokine IL-7. The results revealed NKG2A as a late inhibitory receptor, expressed after repeated cognate antigen stimulations. In contrast, the expression of PD-1, TIGIT and LAG-3 was rapidly induced, hours after first contact and subsequently down regulated during each resting phase. This late, but stable expression kinetics of NKG2A was most similar to that of TIM-3 and CD39. Importantly, single-cell transcriptomics of human tumor-infiltrating lymphocytes (TILs) showed indeed that these receptors were often coexpressed by the same CD8 T cell cluster. Furthermore, NKG2A expression was associated with cell division and was promoted by TGF-β in vitro, although TGF-β signaling was not necessary in a mouse tumor model in vivo. In summary, our data show that PD-1 reflects recent TCR triggering, but that NKG2A is induced after repeated antigen stimulations and represents a late inhibitory receptor. Together with TIM-3 and CD39, NKG2A might thus mark actively dividing tumor-specific TILs., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Gout flares require monosodium urate (MSU) to activate the NLRP3 inflammasome and secrete sufficient IL-1β. However, MSU alone is not sufficient to cause a flare. This is supported by the evidence that most patients with hyperuricemia do not develop gout throughout their lives. Recent studies have shown that, besides MSU, various purine metabolites, including adenosine triphosphate, adenosine diphosphate, and adenosine bind to different purine receptors for regulating IL-1β secretion implicated in the pathogenesis of gout flares. Purine metabolites such as adenosine triphosphate mainly activate the NLRP3 inflammasome through P2X ion channel receptors, which stimulates IL-1β secretion and induces gout flares, while some purine metabolites such as adenosine diphosphate and adenosine mainly act on the G protein-coupled receptors exerting pro-inflammatory or anti-inflammatory effects to regulate the onset and resolution of a gout flare. Given that the purine signaling pathway exerts different regulatory effects on inflammation and that, during the inflammatory process of a gout flare, an altered expression of purine metabolites and their receptors was observed in response to the changes in the internal environment. Thus, the purine signaling pathway is involved in regulating gout flare and resolution. This study was conducted to review and elucidate the role of various purine metabolites and purinergic receptors during the process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Gao and Tao.)

Complex regulation of the immune response is necessary to support effective defense of an organism against hostile invaders and to maintain tolerance to harmless microorganisms and autoantigens. Recent studies revealed previously unappreciated roles of CD71 + erythroid cells (CECs) in regulation of the immune response. CECs physiologically reside in the bone marrow where erythropoiesis takes place. Under stress conditions, CECs are enriched in some organs outside of the bone marrow as a result of extramedullary erythropoiesis. However, the role of CECs goes well beyond the production of erythrocytes. In neonates, increased numbers of CECs contribute to their vulnerability to infectious diseases. On the other side, neonatal CECs suppress activation of immune cells in response to abrupt colonization with commensal microorganisms after delivery. CECs are also enriched in the peripheral blood of pregnant women as well as in the placenta and are responsible for the regulation of feto-maternal tolerance. In patients with cancer, anemia leads to increased frequency of CECs in the peripheral blood contributing to diminished antiviral and antibacterial immunity, as well as to accelerated cancer progression. Moreover, recent studies revealed the role of CECs in HIV and SARS-CoV-2 infections. CECs use a full arsenal of mechanisms to regulate immune response. These cells suppress proinflammatory responses of myeloid cells and T-cell proliferation by the depletion of ʟ-arginine by arginase. Moreover, CECs produce reactive oxygen species to decrease T-cell proliferation. CECs also secrete cytokines, including transforming growth factor β (TGF-β), which promotes T-cell differentiation into regulatory T-cells. Here, we comprehensively describe the role of CECs in orchestrating immune response and indicate some therapeutic approaches that might be used to regulate their effector functions in the treatment of human conditions., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2021 Warszawski Uniwersytet Medyczny. Published by Elsevier Inc. All rights reserved.)

Pathomechanisms in IgA pemphigus are assumed to rely on Fc-dependent cellular activation by antigen-specific IgA autoantibodies; however, models for the disease and more detailed pathophysiologic data are lacking. In this study, we aimed to establish in vitro models of disease for IgA pemphigus, allowing us to study the effects of the interaction of anti-keratinocyte IgA with cell surface FcαRs. Employing multiple in vitro assays, such as a skin cryosection assay and a human skin organ culture model, in this study, we present mechanistic data for the pathogenesis of IgA pemphigus, mediated by anti-desmoglein 3 IgA autoantibodies. Our results reveal that this disease is dependent on FcαR-mediated activation of leukocytes in the epidermis. Importantly, this cell-dependent pathology can be dose-dependently abrogated by peptide-mediated inhibition of FcαR:IgA-Fc interaction, as confirmed in an additional model for IgA-dependent disease, that is, IgA vasculitis. These data suggest that IgA pemphigus can be modeled in vitro and that IgA pemphigus and IgA vasculitis are FcαR-dependent disease entities that can be specifically targeted in these experimental systems., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

For a long time, proteins with enzymatic activity have not been usually considered to carry out other functions different from catalyzing chemical reactions within or outside the cell. Nevertheless, in the last few years several reports have uncovered the participation of numerous enzymes in other processes, placing them in the category of moonlighting proteins. Some moonlighting enzymes have been shown to participate in complex processes such as cell adhesion. Cell adhesion plays a physiological role in multiple processes: it enables cells to establish close contact with one another, allowing communication; it is a key step during cell migration; it is also involved in tightly binding neighboring cells in tissues, etc. Importantly, cell adhesion is also of great importance in pathophysiological scenarios like migration and metastasis establishment of cancer cells. Cell adhesion is strictly regulated through numerous switches: proteins, glycoproteins and other components of the cell membrane. Recently, several cell membrane enzymes have been reported to participate in distinct steps of the cell adhesion process. Here, we review a variety of examples of membrane bound enzymes participating in adhesion of immune cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 López-Cortés, Díaz-Alvarez and Ortega.)