Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells contribute to the body's immune defenses. Current chimeric antigen receptor (CAR)-modified T cell immunotherapy shows strong promise for treating various cancers and infectious diseases. Although CAR-modified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use. To alleviate these disadvantages of CAR-modified T cell immunotherapy, additional cytotoxic cell-mediated immunotherapies are urgently needed. The unique biology of NK cells allows them to serve as a safe, effective, alternative immunotherapeutic strategy to CAR-modified T cells in the clinic. While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood, the formation of the immunological synapse (IS) between CAR-modified T or NK cells and their susceptible target cells is known to be essential. The role of the IS in CAR T and NK cell immunotherapies will allow scientists to harness the power of CAR-modified T and NK cells to treat cancer and infectious diseases. In this review, we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus (HIV), and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy, as well as the importance of understanding the molecular mechanisms of CAR-modified T cell- or NK cell-mediated cytotoxicity and side effects, with a focus on the CAR-modified NK cell IS.

Actin Engine in Immunological Synapse

T cell activation and function require physical contact with antigen presenting cells at a specialized junctional structure known as the immunological synapse. Once formed, the immunological synapse leads to sustained T cell receptor-mediated signalling and stabilized adhesion. High resolution microscopy indeed had a great impact in understanding the function and dynamic structure of immunological synapse. Trends of recent research are now moving towards understanding the mechanical part of immune system, expanding our knowledge in mechanosensitivity, force generation, and biophysics of cell-cell interaction. Actin cytoskeleton plays inevitable role in adaptive immune system, allowing it to bear dynamic and precise characteristics at the same time. The regulation of mechanical engine seems very complicated and overlapping, but it enables cells to be very sensitive to external signals such as surface rigidity. In this review, we focus on actin regulators and how immune cells regulate dynamic actin rearrangement process to drive the formation of immunological synapse.

Contribution of dendritic cell/T cell interactions to triggering and maintaining autoimmunity

Under healthy conditions, there is a balance between tolerance to self-tissue constituents and immunity against foreign antigens. Autoimmunity diseases (AD) take place when that equilibrium is disrupted and the immune response is directed to self-antigens, leading to injury or destruction of host tissues. The mechanisms conducing to the loss of immune tolerance remain largely unknown. The recent appearance of biological therapies has contributed to significant reduction in morbidity. However, currently available therapies are associated with important side effects and work only as palliative treatments. Dendritic cells (DCs) have emerged as key players in developing and maintaining adaptive immunity due to their capacity to prime and modulate T cell function. Therefore, because DCs work as central modulators of immune tolerance, it is likely that alterations in their function can lead to the onset of autoimmune-inflammatory diseases. By modulating DC function, novel pathways in antigen-specific tolerance could be established. In this article, the possible contribution of altered DC-T cell interactions to the onset of autoimmunity are discussed. In addition, we expand on the notion that some of the functions of these cells could be relevant targets for intervening therapies aimed to restore the balance or even prevent the loss of tolerance.

Immunological synapse formation inhibits the apoptosis of macrophages in rheumatoid arthritis / 中华风湿病学杂志

Objective To determine whether macrophages can behave as antigen presenting cells participating the formation of immunological synapse in rheumatoid arthritis (RA) and whether this process can affect the apoptosis. Moreover, this study was aimed to observe the function of cyclophilin A (CypA) in immunological synapse formation and its role in regulating the apoptosis of macrophages. Methods human acute monocytic leukemia cell line (THP-1) induced macrophages were coated with staphylococcal enterotoxin B(SEB) (100 ng/ml) and co-cultured with activated Jurkat T cells (human acute T-cell leukemia cell line), then incubated in the RPMI-1640 for 16 hours to induce apoptosis. The apoptosis of the macrophages were analyzed by flow cytometry by Annexin V-PI staining. The macrophages cultured in the RPMI-1640 alone were used as control. Meanwhile, CypA (200 ng/ml) were added to or not added in order to observe the apoptosis of macrophages. The function of CypA and the apoptosis of macrophages isolated from RA peripheral blood were also investigated through co-culture with CD4+T cells isolated by immunomagnetic beads. Comparisons between groups were performed by two-sample t-tests. Results In the peripheral blood of healthy people and RA patients, the apoptosis of macrophages which participated immunological synapse was (32.9±2.8)%, (24.7±1.6)%, (14.5±1.2)% respectively, which was significantly lower than the apoptosis of macrophages cultured alone [ respectively for (61.4±2.4)%, (45.5±2.6)%, (22.9±1.5)%, (P<0.05) ]. After CypA was added, the apoptosis of macrophages in cell lines, healthy people and RA patients decreased to (27.2±2.1)%, (20.1±1.1)%, (12.9±1.0)%, lower than the apoptosis of macrophages which participated immunological synapse formation (P<0.05). Conclusion In RA, the macrophages participate in the formation of immunological synapse by interacting with CD4+ T cells. They can significantly reduce the apoptosis on themselves. CypA can enhance this effect. These results provide a new theoretical foundation for prolonged survival of macrophages in RA, which can secrete a variety of cytokines to enhance inflammation and joint destruction.

Adenosin deaminasa como molécula coestimuladora y marcador de inmunidad celular / Adenosine deaminase as costimulatory molecule and marker of cellular immunity

La adenosin deaminasa (ADA), es una enzima del metabolismo de las purinas que ha sido objeto de mucho interés debido a que el defecto congénito de esta enzima causa el síndrome de inmunodeficiencia combinada severa. Una de las tres isoformas de la enzima (ecto-ADA) es capaz de unirse a la glicoproteína CD26 y a los receptores de adenosina A1 y A2B. La interacción ADA-CD26 produce una señal coestimuladora en los eventos de activación de las células T y en la secreción de IFN-g, TNF-a e IL-6. Durante dicha activación la actividad de la enzima está regulada de manera positiva por IL-2 e IL-12 y negativamente por IL-4, basado en un mecanismo de translocación. Diversos estudios señalan que los niveles séricos y plasmáticos de ADA se elevan en algunas enfermedades causadas por microorganismos que infectan principalmente a los macrófagos; así como en trastornos hipertensivos, lo cual podría representar un mecanismo compensatorio como consecuencia de la elevación de los niveles de adenosina y la liberación de mediadores hormonales e inflamatorios estimulados por la hipoxia.

Adenosine deaminase (ADA) is an enzyme of purine metabolism which has been the subject of much interest because the congenital defect of this enzyme causes severe combined immunodeficiency syndrome. One of the three isoforms of the enzyme (ecto-ADA) is capable of binding to the glycoprotein CD26 and adenosine receptors A1 and A2B. ADA-CD26 interaction produces a costimulatory signal in the events of T cell activation and secretion of IFN-g, TNF-a and IL-6. During this activation, the enzyme activity is regulated positively by IL-2 and IL-12 and negatively by IL-4, based on the mechanism of translocation. Diverse studies suggest that seric and plasmatic levels of ADA rise in some diseases caused by microorganisms infecting mainly the macrophages and in hypertensive disorders, which may represent a compensatory mechanism resulting from increased adenosine levels and the release of hormones and inflammatory mediators estimulated by hipoxia.

Molecular Mechanisms of Cell-cell Recognition / 生物化学与生物物理进展

Cell-cell recognition is the key for multicellular organisms to survive. This recognition critically depends on protein-protein interactions from opposing cell surfaces. Recent structural investigations reveal unique features of these cell surface receptors and how they interact. These interactions are specific, but usually relatively weak, with more hydrophilic forces involved in binding. The receptors appear to have specialized ways to present their key interacting elements for ligand-binding from the cell surface. Cell-cell contacts are multivalent. A large group of cell surface molecules are engaged in interactions. Characteristic weak interactions make possible for each individual molecule pair within the group to constantly associate-dissociate-reassociate, such that the cell-cell recognition becomes a dynamic process. The immunological synapse is a good example for immune receptors to be orchestrated in performing immunological function in a collective fashion.

Reorientation of T cell receptors during immunological synapse formation:a vortex-driven model / 中国免疫学杂志

Objective:To develop the mechanistic model for the reorientation of T cell receptors during immunological synapse formation.Methods:Based on the theory of energy transfer during double-molecular reactions in the context of classical fluid mechanics,a vortex-driven model was proposed where in the coupled receptor/ligand molecules within the immunological synapse recruit the T cell receptors.Results:The model results indicated that driven by the consecutive vortexes with specific combinations of strengths and acting frequencies of vortexes,TCR transport speed can reach the values matching up to the experimental measurements(0.04-0.1 ?m/s).Conclusion:The model demonstrated that during the coupling,the membrane-tethered receptor-ligand pairs may transform their binding energies into the rotational energies of the reactants,thereby leading to the vortexes of the surrounding water continuum insider and outside the T cell,and these resulting vortexes may function as the engines for the reorientation of T cell receptors.