Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer ...initiation. Genetic loss of Gclm prevents a tumor’s ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.
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•The GSH antioxidant pathway is required for cancer initiation•After cancer initiation, GSH is dispensable due to alternative antioxidant pathways•The TXN antioxidant pathway is upregulated in tumors•Inhibition of both GSH and TXN pathways causes synergistic cancer cell death
Harris et al. show that the antioxidant glutathione (GSH) is required for cancer initiation but not for established tumors partly due to upregulation of the thioredoxin (TXN) antioxidant pathway in the latter. Consequently, blocking both GSH and TXN pathways synergistically inhibits tumor growth.
•Immune cells combating chronic infection express numerous ‘check point’ receptors in human patients.•Inhibition of these receptors restores the function of exhausted T cells in chronically infected ...humans and animals.•Initial case reports in humans suggest targeting checkpoint inhibitors in HBV, HCV, and HIV could repress viral loads.•Newly identified inhibitory receptors may synergize to induce exhaustion, and therefore multiple pathways could be targeted to facilitate immunity.
The recent successes of immune check point targeting therapies in treating cancer patients has driven a resurgence of interest in targeting these pathways in chronically infected patients. While still in early stages, basic and clinical data suggest that blockade of CTLA-4 and PD-1 can be beneficial in the treatment of chronic HIV, HBV, and HCV infection, as well as other chronic maladies. Furthermore, novel inhibitory receptors such as Tim-3, LAG-3, and TIGIT are the potential next wave of check points that can be manipulated for the treatment of chronic infection. Blockade of these pathways influences more than simply T cell responses, and may provide new therapeutic options for chronically infected patients.
Stress contributes to infection and cancer susceptibility, but the mediating mechanisms are still being elucidated. CD8 T cells are critical players in antiviral and antitumor immune responses. A ...recent study by Globig et al., together with a growing body of literature, link norepinephrine produced during the stress response to CD8 T cell dysfunction.
Stress contributes to infection and cancer susceptibility, but the mediating mechanisms are still being elucidated. CD8 T cells are critical players in antiviral and antitumor immune responses. A recent study by Globig et al., together with a growing body of literature, link norepinephrine produced during the stress response to CD8 T cell dysfunction.
Recurrent Clostridioides difficile infection (CDI) results in significant morbidity and mortality. We previously established that CDI in mice does not protect against reinfection and is associated ...with poor pathogen-specific B cell memory (Bmem), recapitulating our observations with human Bmem. Here, we demonstrate that the secreted toxin TcdB2 is responsible for subversion of Bmem responses. TcdB2 from an endemic C. difficile strain delayed immunoglobulin G (IgG) class switch following vaccination, attenuated IgG recall to a vaccine booster, and prevented germinal center formation. The mechanism of TcdB2 action included increased B cell CXCR4 expression and responsiveness to its ligand CXCL12, accounting for altered cell migration and a failure of germinal center-dependent Bmem. These results were reproduced in a C. difficile infection model, and a US Food and Drug Administration (FDA)-approved CXCR4-blocking drug rescued germinal center formation. We therefore provide mechanistic insights into C. difficile-associated pathogenesis and illuminate a target for clinical intervention to limit recurrent disease.
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•C. difficile toxin B (TcdB2) suppresses antibody recall responses•TcdB2 blocks germinal center formation•TcdB2 alters B cell CXCR4-mediated cell migration•A CXCR4-blocking drug rescues germinal center formation
Norman et al. use mouse models of C. difficile vaccination and infection to delineate a CXCR4-dependent mechanism by which the secreted toxin TcdB2 suppresses germinal center formation and antibody recall responses. Germinal centers were rescued by a CXCR4-blocking drug, suggesting a therapeutic avenue for prevention of recurrent C. difficile infection.
CD8 T-cell responses are critical for protection against intracellular pathogens and tumors. The induction and properties of these responses are governed by a series of integrated processes that rely ...heavily on cell–cell interactions. Intercellular adhesion molecule (ICAM)-1 functions to enhance the strength of antigenic stimulation, extend the duration of contact with antigen-presenting cells, and augment cytokine signals, which are all factors that influence peripheral CD8 T-cell differentiation. Although previous studies suggest that ICAM-1 is essential for establishing memory T-cell populations following peptide immunization, the roles of ICAM-1 in antiviral cellular immunity are less well understood. Here we show that, following a prototypic acute viral infection, the formation and maintenance of memory-phenotype CD127 ʰⁱ, KLRG-1 ˡᵒ CD8 T cells does not require ICAM-1. Nevertheless, ICAM-1 expression on nonlymphocytes dictates the phenotypic and functional attributes of the antiviral CD8 T-cell populations that develop and promotes the gradual attrition of residual effector-like CD127 ˡᵒ, KLRG-1 ʰⁱ CD8 T cells during the memory phase of the response. Although memory T cells do emerge and are maintained if ICAM-1 expression is abolished, the secondary proliferative capacity of these T cells is severely curtailed. Collectively, these studies reveal potential dual roles for ICAM-1 in both promoting the decay of effector responses and programming the sensitivity of memory CD8 T cells to secondary stimuli.
Interleukin-21 (IL-21) is a cytokine that has broad effects on both innate and adaptive immune responses. The roles of IL-21 in determining immunity to infections are currently being defined, and ...notably, it has been shown that IL-21 is most critical for sustaining T cell responses during chronic viral infections. This article discusses our current understanding of the immunobiology of IL-21, as well as its known and potential roles in influencing immunity to infections.
T cells at the interface of neuroimmune communication Reel, Jessica M.; Abbadi, Jumana; Cox, Maureen A.
Journal of allergy and clinical immunology,
April 2024, 2024-Apr, 2024-04-00, 20240401, Letnik:
153, Številka:
4
Journal Article
Recenzirano
The immune system protects the host from infection and works to heal damaged tissue after infection or injury. There is increasing evidence that the immune system and the nervous system work in ...concert to achieve these goals. The sensory nervous system senses injury, infection, and inflammation, which results in a direct pain signal. Direct activation of peripheral sensory nerves can drive an inflammatory response in the skin. Immune cells express receptors for numerous transmitters released from sensory and autonomic nerves, which allows the nervous system to communicate directly with the immune system. This communication is bidirectional because immune cells can also produce neurotransmitters. Both innate and adaptive immune cells respond to neuronal signaling, but T cells appear to be at the helm of neuroimmune communication.
T-cell exhaustion is characterized by the stepwise and progressive loss of T-cell functions and can culminate in the physical deletion of the responding cells. Exhaustion is well-defined during ...chronic lymphocytic choriomeningitis virus infection and commonly develops under conditions of antigen-persistence, which occur following many chronic infections that are of significant public health concern including hepatitis B virus, hepatitis C virus and human immunodeficiency virus infections, as well as during tumour outgrowth. Exhaustion is not a uniformly disabled setting as a gradation of phenotypic and functional defects can manifest, and these cells are distinct from prototypic effector, memory and also anergic T cells. We are gaining insights into the extrinsic and intrinsic factors that determine the severity of exhaustion. These include the duration and magnitude of antigenic activation, availability of CD4 T-cell help, the levels of stimulatory and suppressive cytokines, as well as the expression of activatory and inhibitory receptors. More information is now becoming available regarding the molecular mechanisms that attenuate the responsiveness of exhausted T cells. As the parameters that dictate exhaustion are more thoroughly defined, this is fostering the development of methods that prevent and rejuvenate functionally inferior responses. In this article we discuss our current understanding of the properties of exhausted T cells and the mechanisms that promote and maintain this state.
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