Ezrin, radixin and moesin proteins (ERMs) are plasma membrane (PM) organizers that link the actin cytoskeleton to the cytoplasmic tail of transmembrane proteins, many of which are adhesion receptors, ...in order to regulate the formation of F-actin-based structures (e.g., microspikes and microvilli). ERMs also effect transmission of signals from the PM into the cell, an action mainly exerted through the compartmentalized activation of the small Rho GTPases Rho, Rac and Cdc42. Ezrin and moesin are the ERMs more highly expressed in leukocytes, and although they do not always share functions, both are mainly regulated through phosphatidylinositol 4,5-bisphosphate (PIP
) binding to the N-terminal band 4.1 protein-ERM (FERM) domain and phosphorylation of a conserved Thr in the C-terminal ERM association domain (C-ERMAD), exerting their functions through a wide assortment of mechanisms. In this review we will discuss some of these mechanisms, focusing on how they regulate polarization and migration in leukocytes, and formation of actin-based cellular structures like the phagocytic cup-endosome and the immune synapse in macrophages/neutrophils and lymphocytes, respectively, which represent essential aspects of the effector immune response.
Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). The progression, from the early stages of the disease as monoclonal ...gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM and occasionally extramedullary disease, is drastically affected by the tumor microenvironment (TME). Soluble factors and direct cell-cell interactions regulate MM plasma cell trafficking and homing to the BM niche. Mesenchymal stromal cells, osteoclasts, osteoblasts, myeloid and lymphoid cells present in the BM create a unique milieu that favors MM plasma cell immune evasion and promotes disease progression. Moreover, TME is implicated in malignant cell protection against anti-tumor therapy. This review describes the main cellular and non-cellular components located in the BM, which condition the immunosuppressive environment and lead the MM establishment and progression.
Despite the impressive results of autologous CAR-T cell therapy in refractory B lymphoproliferative diseases, CAR-NK immunotherapy emerges as a safer, faster, and cost-effective approach with no ...signs of severe toxicities as described for CAR-T cells. Permanently scrutinized for its efficacy, recent promising data in CAR-NK clinical trials point out the achievement of deep, high-quality responses, thus confirming its potential clinical use. Although CAR-NK cell therapy is not significantly affected by the loss or downregulation of its CAR tumor target, as in the case of CAR-T cell, a plethora of common additional tumor intrinsic or extrinsic mechanisms that could also disable NK cell function have been described. Therefore, considering lessons learned from CAR-T cell therapy, the emergence of CAR-NK cell therapy resistance can also be envisioned. In this review we highlight the processes that could be involved in its development, focusing on cytokine addiction and potential fratricide during manufacturing, poor tumor trafficking, exhaustion within the tumor microenvironment (TME), and NK cell short
in vivo
persistence on account of the limited expansion, replicative senescence, and rejection by patient’s immune system after lymphodepletion recovery. Finally, we outline new actively explored alternatives to overcome these resistance mechanisms, with a special emphasis on CRISPR/Cas9 mediated genetic engineering approaches, a promising platform to optimize CAR-NK cell function to eradicate refractory cancers.
Nitric oxide (NO) is a key messenger in the pathogenesis of inflammation, linking innate and adaptive immunity. By targeting signaling molecules, NO from inducible NO synthase (iNOS) and endothelial ...(e)NOS affects T helper cell differentiation and the effector functions of T lymphocytes, and is a potential target for therapeutic manipulation. In this review we discuss the regulatory actions exerted by NO on T cell functions, focusing on S-nitrosylation as an important post-translational modification by which NO acts as a signaling molecule during T cell-mediated immunity. We also present recent findings showing novel mechanisms through which NO regulates the activation of human T cells, and consider their potential in strategies to treat tumoral, allergic, and autoimmune diseases.
NO is a key regulator of adaptive immunity that influences both T cell activation and the fate decision programs that drive T helper cell differentiation and the development of allergic and autoimmune diseases.
Important differences between the actions mediated by NO generated from either exogenous cellular sources or T lymphocytes, and between human and mouse species – with respect to the amount of NO produced and the regulation of NOS expression – can explain the dual actions exerted by NO in T cell-mediated adaptive immunity.
The pathways through which NO regulates the response of T lymphocytes in adaptive immunity are expanding towards cGMP-independent mechanisms, including compartmentalized short-range protein S-nitrosylation.
Recent studies have demonstrated that the production of NO is compartmentalized at the immune synapse of human T cells, and positively regulates T cell activation through S-nitrosylation-dependent mechanisms.
Preclinical studies and clinical trials have opened new horizons for the application of NO sources and inhibitors to regulate T cell functions for the treatment of cancer and allergic and autoimmune diseases.
The actin cytoskeleton coordinates the organization of signaling microclusters at the immune synapse (IS); however, the mechanisms involved remain poorly understood. We show here that nitric oxide ...(NO) generated by endothelial nitric oxide synthase (eNOS) controls the coalescence of protein kinase C-θ (PKC-θ) at the central supramolecular activation cluster (c-SMAC) of the IS. eNOS translocated with the Golgi to the IS and partially colocalized with F-actin around the c-SMAC. This resulted in reduced actin polymerization and centripetal retrograde flow of β-actin and PKC-θ from the lamellipodium-like distal (d)-SMAC, promoting PKC-θ activation. Furthermore, eNOS-derived NO S-nitrosylated β-actin on Cys374 and impaired actin binding to profilin-1 (PFN1), as confirmed with the transnitrosylating agent S-nitroso-L-cysteine (Cys-NO). The importance of NO and the formation of PFN1-actin complexes on the regulation of PKC-θ was corroborated by overexpression of PFN1- and actin-binding defective mutants of β-actin (C374S) and PFN1 (H119E), respectively, which reduced the coalescence of PKC-θ at the c-SMAC. These findings unveil a novel NO-dependent mechanism by which the actin cytoskeleton controls the organization and activation of signaling microclusters at the IS.
In the immune system, nitric oxide (NO) has been mainly associated with antibacterial defenses exerted through oxidative, nitrosative, and nitrative stress and signal transduction through cyclic ...GMP-dependent mechanisms. However, S-nitrosylation is emerging as a post-translational modification (PTM) involved in NO-mediated cell signaling.
Precise roles for S-nitrosylation in signaling pathways have been described both for innate and adaptive immunity. Denitrosylation may protect macrophages from their own S-nitrosylation, while maintaining nitrosative stress compartmentalized in the phagosomes. Nitrosothiols have also been shown to be beneficial in experimental models of autoimmune diseases, mainly through their role in modulating T-cell differentiation and function.
Relationship between S-nitrosylation, other thiol redox PTMs, and other NO-signaling pathways has not been always taken into account, particularly in the context of immune responses. Methods for assaying S-nitrosylation in individual proteins and proteomic approaches to study the S-nitrosoproteome are constantly being improved, which helps to move this field forward.
Integrated studies of signaling pathways in the immune system should consider whether S-nitrosylation/denitrosylation processes are among the PTMs influencing the activity of key signaling and adaptor proteins. Studies in pathophysiological scenarios will also be of interest to put these mechanisms into broader contexts. Interventions modulating nitrosothiol levels in autoimmune disease could be investigated with a view to developing new therapies.
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