Co-signaling surface receptors: regulators of adaptive immune response. Comment on Shen H, et al. "Co-signaling receptors regulate T-cell plasticity and immune tolerance". Frontiers in Bioscience-Landmark. 2019; 24: 96-132.

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Antigen Presenting Cells and Stromal Cells Trigger Human Natural Killer Lymphocytes to Autoreactivity: Evidence for the Involvement of Natural Cytotoxicity Receptors (NCR) and NKG2D

Human natural killer (NK) lymphocytes should not damage autologous cells due to the engagement of inhibitory receptor superfamily (IRS) members by HLA-I. Nevertheless, NK cells kill self cells expressing low levels or lacking HLA-I, as it may occur during viral infections (missing-self hypothesis). Herein, we show that human NK cells can be activated upon binding with self antigen presenting cells or stromal cells despite the expression of HLA-I. Indeed, NK cells can kill and produce pro-inflammatory and regulating cytokines as IFN-γ, TNF-α and IL10 during interaction with autologous dendritic cells or bone marrow stromal cells or skin fibroblasts. The killing of antigen presenting and stromal cells is dependent on LFA1/ICAM1 interaction. Further, the natural cytotoxicity receptors (NCR) NKp30 and NKp46 are responsible for the delivery of lethal hit to DC, whereas NKG2D activating receptor, the ligand of the MHC-related molecule MIC-A and the UL16 binding protein, is involved in stromal cell killing. These findings indicate that different activating receptors are involved in cell to self cell interaction. Finally, NK cells can revert the veto effect of stromal cells on mixed lymphocyte reaction further supporting the idea that NK cells may alter the interaction between T lymphocytes and microenvironment leading to autoreactivity

Stress immunity in lymphomas: mesenchymal cells as a target of therapy.

Abstract The role of lymphocytes in eliminating lymphoma cells is based on the interaction between activating receptors on lymphocytes and target surface ligands on lymphoma cells. Stress-related immunity can be triggered both in Hodgkin's (HL) and non-Hodgkin lymphomas (NHL), through the activation of the NKG2D receptor on CD8+ T and gammadelta T lymphocytes, by NKG2D-ligands (NKG2D-L), as the MHC class-I related molecules MIC-A/B and the UL16-binding proteins 1-4 (ULBPs), expressed on lymphoma cells. Furthermore, NKG2D-L can be shed and interact with NKG2D on effector lymphocytes affecting the recognition of lymphoma cells. Proteolytic cleavage of MIC-A is known to depend on the thiol isomerase ERp5 and the disintegrins and metalloproteinases ADAM10 and ADAM17, which also cleave ULPBs. Mesenchymal stromal cells (MSC) are relevant in regulating effector T lymphocytes-mediated lymphoma surveillance. Indeed, MSC can be seen as targets of potential new therapeutic schemes acting on lymphoma microenvironment, to redirect the stress immune response and avoid escape strategies, by inducing stress molecules, inhibiting sheddase activity, shifting cytokine production to Th1 pattern and blocking Treg differentiation

Anti-cancer γδ T lymphocytes: contradictory past and promising future

Recent anti-cancer strategies are based on the stimulation of anti-tumor immune reaction, exploiting distinct lymphocyte subsets. Among them, γδ T cells represent optimal anti-cancer candidates, especially in those tissues where they are highly localized, such as the respiratory or gastrointestinal tract. One important challenge has been the identification of stimulating drugs able to induce and maintain γδ T cell-mediated anti-cancer immune response. Amino-bisphosphonates (N-BPs) have been largely employed in anti-cancer clinical trials due to their ability to upregulate the accumulation of pyrophosphates that promote the activation of Vγ9Vδ2 T cells. This activation depends on the butyrophilin A family, which is crucial in contributing to Vγ9Vδ2 T cells stimulation but is not equally expressed in all cancer tissues. Thus, the clinical outcome of such treatments is still a challenge. In this viewpoint, a critical picture of γδ T cells as effective anti-cancer effectors is designed, with a specific focus on the best immune-stimulating therapeutic schemes involving this lymphocyte subset and the tools available to measure their efficacy and presence in tumor tissues. Some pre-clinical models, useful to measure γδ T cell anti-cancer potential and their response to stimulating drugs, therapeutic monoclonal antibodies, or bispecific antibodies are described. Computerized imaging and digital pathology are also proposed as a help in the identification of co-stimulatory molecules and localization of γδ T cell effectors. Finally, two types of novel drug preparation are proposed: nanoparticles loaded with N-BPs and pro-drug formulations that enhance the effectiveness of γδ T lymphocyte stimulation

HIV-1 Tat Triggers TGF-β Production and NK Cell Apoptosis that is Prevented by Pertussis Toxin B

Herein, we show that PTX-B and its non-toxic mutant PT9K/129G inhibit transcription and secretion of TGF-β elicited by HIV-1 Tat in NK cells. Moreover, Tat strongly activates the cJun component of the multimolecular complex AP-1, while TGF-β triggers cFos and cJun. Treatment of NK cells In turn,with PTX-B or PT9K/129G inhibits Tat and TGF-β-induced activation of AP-1. TGF-β enhances starvation-induced NK cell apoptosis, reduces the transcription of the antiapoptotic protein Bcl-2 and inhibits Akt phosphorylation induced by oligomerization of the triggering NK cell receptor NKG2D. All these TGF-β-mediated effects are prevented by PTX-B or PT9K/129G, through a PI-3K-dependent mechanism. Finally, PTX-B and PT9K/129G upregulate Bcl-xL, the isoform of Bcl-x that protects cells from starvation-induced apoptosis. Of note, in NK cells from patients with HIV-1 infection, mRNA expression of Bcl-2 and Bcl-xL was consistently lower than that of healthy donors; interestingly, TGF-β and Tat were detected in the sera of these patients. These data suggest that Tat-induced TGF-β production and the consequent NK cell failure, possibly occurring during early HIV-1 infection, may be regulated by PTX-B and PT9K/129G

Social signals: from theory to applications

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Imatinib mesylate can help to direct natural immunity toward an anti-leukemic reactivity by acting on the bone marrow microenvironment

We discuss our recent findings on the increase, in chronic myeloid leukemia patients treated with imatinib, of B1 lymphocytes producing IgM anti-O-linked sugars expressed by leukemic cells, paralleled by increased B-stimulating cytokines. We propose that one important effect of imatinib treatment is due to the remodelling of bone marrow microenvironment

NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1

AbstractInteraction of natural killer (NK) cells with autologous immature dendritic cells (DCs) results in reciprocal activation; however, the underlying mechanisms are so far elusive. We show here that NK cells trigger immature DCs to polarize and secrete interleukin 18 (IL-18), a cytokine lacking a secretory leader sequence. This occurs through a Ca2+-dependent and tubulin-mediated recruitment of IL-18-containing secretory lysosomes toward the adhering NK cell. Lysosome exocytosis and IL-18 secretion are restricted at the synaptic cleft, thus allowing activation of the interacting NK cells without spreading of the cytokine. In turn, DC-activated NK cells secrete the proinflammatory cytokine high mobility group B1 (HMGB1), which induces DC maturation and protects DCs from lysis. Also HMGB1 is a leaderless cytokine that undergoes regulated secretion. Differently from IL-18, soluble HMGB1 is consistently detected in NK/DC supernatants. These data point to secretion of leaderless cytokines as a key event for the reciprocal activation of NK cells and DCs. DCs initiate NK cell activation by targeted delivery of IL-18, thus instructing NK cells in the absence of adaptive-type cytokines; in turn, activated NK cells release HMGB1, which promotes inflammation and induces DC maturation, thus favoring the onset of the adaptive immune response. (Blood. 2005;106:609-616

How Soundtracks Shape What We See: Analyzing the Influence of Music on Visual Scenes Through Self-Assessment, Eye Tracking, and Pupillometry

This article presents two studies that deepen the theme of how soundtracks shape our interpretation of audiovisuals. Embracing a multivariate perspective, Study 1 (N = 118) demonstrated, through an online between-subjects experiment, that two different music scores (melancholic vs. anxious) deeply affected the interpretations of an unknown movie scene in terms of empathy felt toward the main character, impressions of his personality, plot anticipations, and perception of the environment of the scene. With the melancholic music, participants felt empathy toward the character, viewing him as more agreeable and introverted, more oriented to memories than to decisions, while perceiving the environment as cozier. An almost opposite pattern emerged with the anxious music. In Study 2 (N = 92), we replicated the experiment in our lab but with the addition of eye-tracking and pupillometric measurements. Results of Study 1 were largely replicated; moreover, we proved that the anxious score, by increasing the participants’ vigilance and state of alert (wider pupil dilation), favored greater attention to minor details, as in the case of another character who was very hard to be noticed (more time spent on his figure). Results highlight the pervasive nature of the influence of music within the process of interpretation of visual scenes