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Perforin protein (pfp) and/or IFN- knockout (KO) mice predominately develop B-cell lymphomas, especially after 1?year of age (older animals) with a combination of pfp and IFN- KO inducing an early onset of lymphoma, suggesting a synergistic immunosurveillance effect (37)

Perforin protein (pfp) and/or IFN- knockout (KO) mice predominately develop B-cell lymphomas, especially after 1?year of age (older animals) with a combination of pfp and IFN- KO inducing an early onset of lymphoma, suggesting a synergistic immunosurveillance effect (37). responses to viral infections and malignancy. NK cells can modulate the adaptive immune response their role in dendritic cell (DC) maturation, removal of immature tolerogenic DCs, and their ability to produce immunoregulatory cytokines. NK cells are therefore poised as attractive therapeutic targets that can be harnessed to control or obvious both HIV and HIV-associated malignancies. To date, features of the tumor microenvironment and the development Sulfaquinoxaline sodium salt of NK-cell function among individuals with HIV-related malignancies remain unclear and may be unique from malignancies observed in uninfected persons. This review intends to uncouple anti-HIV and antitumor NK-cell features that can be manipulated to halt the development of HIV disease and HIV-associated malignancies and serve as potential preventative and curative immunotherapeutic options. induction of Fas/FasL-dependent or TRAIL-dependent apoptotic signals. In addition, a minority of NK cells express the FcRIIIA receptor (CD16) that binds to the constant (Fc) domain name of IgG antibodies that can bind to viral antigens expressed on the surface of infected cells. This antibody conjugation of NK-cell and antibody-coated target cell, strongly mediating NK-cell activation, is known as antibody-dependent cell-mediated cytotoxicity (ADCC) (27). A distinct subset of CD56bright cytokine-producing NK cells with a limited cytotoxic capacity is usually more abundantly present in lymph nodes (28). By generating IFN-, TNF-, IL-10, and chemokines, this NK subset predominantly modulates other subsets of lymphocytes, thereby regulating dendritic cell maturation, differentiation of helper T cells, and B- and T-cell-specific immune responses (29, 30). To understand the NK-cell effector functions, it is paramount to take into consideration Rabbit Polyclonal to ARHGEF11 the balance between activating and inhibitory signals (31) that drive NK-cell cytotoxicity. NK-cell activation relies on stimulatory signals capable of overcoming the constant inhibitory state that is usually managed by signaling through inhibitory receptors. Self-recognition of MHC-I proteins through C-type lectin receptor NKG2A and inhibitory killer cell immunoglobulin-like receptors (KIRs) represent the physiological conversation between NK and target cells. The absence of acknowledgement of self by inhibitory receptors characterizes the missing-self phenomenon and lowers the activating threshold. NK cells become more susceptible to activation, especially if activating molecules Sulfaquinoxaline sodium salt are expressed in infected or transformed target cells and recognized by activating receptors, characterizing the altered-self phenomenon. Activating C-type lectin receptor NKG2D recognizes the altered self-state of infected or transformed cells and triggers NK-cell cytolytic activity. Other surface molecules, such as natural cytotoxic receptors Nkp30, Nkp44, and Nkp46, and activating KIRs also contribute to NK-cell activation process and are crucial to determine whether NK cells will be activated to target infected or transformed cells (27, 31). Both HIV contamination and oncogenesis lead to a downregulation of surface MHC-I expression as a way to avoid T-cell acknowledgement but in change renders target cells more susceptible to NK-cell-mediated cytolysis. However, HIV has developed immune evasion mechanisms the viral protein Nef, thereby leading to preferential downregulation of HLA-A and -B, and preserving expression of HLA-C and -E (32). Sulfaquinoxaline sodium salt Therefore, HIV prevents NK activation as well as CTL recognition of infected cells. Besides interfering with self-recognition, HIV infection and cancer can induce expression of stress signaling molecules, in particular MHC class I polypeptide-related sequence A/B (MICA/MICB). More importantly, HIV leads to persistent activation and consequently T cell and NK-cell immune exhaustion. Despite viral suppression and normal CD4 T-cell counts in the majority of HIV-infected persons on ART, NK-cell phenotype and functionality are not fully restored, suggesting that these individuals may be more susceptible to long-term comorbidities associated with immune dysfunction, such as HIV-related malignancies (33). The Interplay between the Tumor Microenvironment and NK-Cell Immunity The process by which the immune system can promote or suppress tumor growth and development is based on animal models and data from cancer patients and has evolved to define the concept of cancer immunoediting (34). Tumor immunoediting is comprised of three phases: elimination, equilibrium, and escape. The elimination phase is when immune cells target cancer cells that succeeded in overcoming intrinsic tumor suppressor mechanisms. If tumor elimination is only partially achieved, a state of equilibrium between malignant cells and the immune system ensues. Tumor cells can become dormant or accumulate mutations, while the immune system continues to exert selective pressure, thereby controlling tumor progress temporarily or eventually eliminating the cancer cells. If elimination does not occur, tumor cell variants resistant to the existent immune response eventually give rise to tumor progression, thereby initiating the escape phase.