RESUMEN
The activation of natural killer (NK) cells depends on a change in the balance of signals from inhibitory and activating receptors. The activation threshold values of NK cells are thought to be set by engagement of inhibitory receptors during development. Here, we found that the activating receptor NKG2D specifically set the activation threshold for the activating receptor NCR1 through a process that required the adaptor DAP12. As a result, NKGD2-deficient (Klrk1-/-) mice controlled tumors and cytomegalovirus infection better than wild-type controls through the NCR1-induced production of the cytokine IFN-γ. Expression of NKG2D before the immature NK cell stage increased expression of the adaptor CD3ζ. Reduced expression of CD3ζ in Klrk1-/- mice was associated with enhanced signal transduction through NCR1, and CD3ζ deficiency resulted in hyper-responsiveness to stimulation via NCR1. Thus, an activating receptor developmentally set the activity of another activating receptor on NK cells and determined NK cell reactivity to cellular threats.
Asunto(s)
Antígenos Ly/inmunología , Citotoxicidad Inmunológica/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Receptor 1 Gatillante de la Citotoxidad Natural/inmunología , Animales , Ratones , Ratones NoqueadosRESUMEN
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly common complication of obesity, affecting over a quarter of the global adult population. A key event in the pathophysiology of MASLD is the development of metabolic-associated steatohepatitis (MASH), which greatly increases the chances of developing cirrhosis and hepatocellular carcinoma. The underlying cause of MASH is multifactorial, but accumulating evidence indicates that the inflammatory process in the hepatic microenvironment typically follows a pattern that can be roughly divided into three stages: (1) Detection of hepatocyte stress by tissue-resident immune cells including γδ T cells and CD4-CD8- double-negative T cells, followed by their secretion of pro-inflammatory mediators, most notably IL-17A. (2) Recruitment of pro-inflammatory cells, mostly of the myeloid lineage, and initiation of inflammation through secretion of effector-type cytokines such as TNF, TGF-ß, and IL-1ß. (3) Escalation of the inflammatory response by recruitment of lymphocytes including Th17, CD8 T, and B cells leading to chronic inflammation, hepatic stellate cell activation, and fibrosis. Here we will discuss these three stages and how they are consecutively linked like falling domino tiles to the pathophysiology of MASH. Moreover, we will highlight the clinical potential of inflammation as a biomarker and therapeutic target for the treatment of MASLD.
Asunto(s)
Hígado Graso , Neoplasias Hepáticas , Enfermedades Metabólicas , Adulto , Humanos , Linfocitos B , Inflamación , Microambiente TumoralRESUMEN
NKG2D is a potent activating receptor that is expressed on cytotoxic immune cells such as CD8 T and NK cells, where it promotes cytotoxicity after binding stress ligands on infected or transformed cells. On NK cell precursors NKG2D modulates proliferation and maturation. Previously, we observed that NKG2D deficiency affects peripheral B cell numbers. In this study, we show that NKG2D regulates B1a cell development and function. We find that mice deficient for NKG2D have a strong reduction of B1a cell numbers. As a result, NKG2D-deficient mice produce significantly less Ag-specific IgM Abs upon immunization with T cell-independent Ags, and they are more susceptible to Gram-negative sepsis. Klrk1-/- B1a cells are also functionally impaired and they fail to provide protection against Francisella novicida upon adoptive transfer. Using mixed bone marrow chimeric mice, we show that the impact of NKG2D deficiency on B1a cell development is cell intrinsic. No changes in homeostatic turnover and homing of B cells were detectable, limiting the effects of NKG2D to modulation of the hematopoietic development of B1a cells. Using conditional ablation, we demonstrate that the effect of NKG2D on B1a cell development occurs at a developmental stage that precedes the common lymphoid progenitor. Our findings reveal an unexpected new role for NKG2D in the regulation of B1a cell development. The protective effects of this activating receptor therefore reach beyond that of cytotoxic cells, stimulating the immune system to fight bacterial infections by promoting development of innate-like B cells.
Asunto(s)
Linfocitos B/fisiología , Diferenciación Celular , Infecciones por Bacterias Gramnegativas/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Traslado Adoptivo , Animales , Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Francisella/inmunología , Infecciones por Bacterias Gramnegativas/prevención & control , Antígenos de Histocompatibilidad Clase I/inmunología , Inmunoglobulina M/inmunología , Células Asesinas Naturales/inmunología , Ratones , Subfamilia K de Receptores Similares a Lectina de Células NK/deficiencia , Bazo/citología , Bazo/inmunologíaRESUMEN
NKp46/NCR1 is an activating NK-cell receptor implicated in the control of various viral and bacterial infections. Recent findings also suggest that it plays a role in shaping the adaptive immune response to pathogens. Using NCR1-deficient (NCR1gfp/gfp ) mice, we provide evidence for the role of NCR1 in antibody response to mouse cytomegalovirus infection (MCMV). The absence of NCR1 resulted in impaired maturation, function and NK-cell migration to regional lymph nodes. In addition, CD4+ T-cell activation and follicular helper T-cell (Tfh) generation were reduced, leading to inferior germinal center (GC) B-cell maturation. As a consequence, NCR1gfp/gfp mice produced lower amounts of MCMV-specific antibodies upon infection, which correlated with lower number of virus-specific antibody secreting cells in analyzed lymph nodes.
Asunto(s)
Antígenos Ly/metabolismo , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Centro Germinal/inmunología , Infecciones por Herpesviridae/inmunología , Células Asesinas Naturales/inmunología , Muromegalovirus/inmunología , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Animales , Anticuerpos Antivirales/sangre , Antígenos Ly/genética , Diferenciación Celular , Movimiento Celular , Células Cultivadas , Inmunidad Humoral , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptor 1 Gatillante de la Citotoxidad Natural/genéticaRESUMEN
Natural killer group 2 member D (NKG2D) is an activating receptor that is expressed on most cytotoxic cells of the immune system, including NK cells, γδ, and CD8+ T cells. It is still a matter of debate whether and how NKG2D mediates priming of CD8+ T cells in vivo, due to a lack of studies where NKG2D is eliminated exclusively in these cells. Here, we studied the impact of NKG2D on effector CD8+ T-cell formation. NKG2D deficiency that is restricted to murine CD8+ T cells did not impair antigen-specific T-cell expansion following mouse CMV and lymphocytic choriomeningitis virus infection, but reduced their capacity to produce cytokines. Upon infection, conventional dendritic cells induce NKG2D ligands, which drive cytokine production on CD8+ T cells via the Dap10 signaling pathway. T-cell development, homing, and proliferation were not affected by NKG2D deficiency and cytotoxicity was only impaired when strong T-cell receptor (TCR) stimuli were used. Transfer of antigen-specific CD8+ T cells demonstrated that NKG2D deficiency attenuated their capacity to reduce viral loads. The inability of NKG2D-deficient cells to produce cytokines could be overcome with injection of IL-15 superagonist during priming. In summary, our data show that NKG2D has a nonredundant role in priming of CD8+ T cells to produce antiviral cytokines.
Asunto(s)
Infecciones por Arenaviridae/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Infecciones por Herpesviridae/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Animales , Citocinas/biosíntesis , Citotoxicidad Inmunológica , Células Dendríticas/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Muromegalovirus , Subfamilia K de Receptores Similares a Lectina de Células NK/deficiencia , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Transducción de SeñalRESUMEN
Memory formation of activated CD8 T cells is the result of a specific combination of signals that promote long-term survival and inhibit differentiation into effector cells. Much is known about initial cues that drive memory formation, but it is poorly understood which signals are essential during the intermediate stages before terminal differentiation. NKG2D is an activating coreceptor on Ag-experienced CD8 T cells that promotes effector cell functions. Its role in memory formation is currently unknown. In this study, we show that NKG2D controls formation of CD8 memory T cells by promoting survival of precursor cells. We demonstrate that NKG2D enhances IL-15-mediated PI3K signaling of activated CD8 T cells, in a specific phase of memory cell commitment, after activation but before terminal differentiation. This signal is essential for the induction of prosurvival protein Mcl-1 and precursor cell survival. In vivo, NKG2D deficiency results in reduced memory cell formation and impaired protection against reinfection. Our findings show a new role for PI3K and the NKG2D/IL-15 axis in an underappreciated stage of effector to memory cell transition that is essential for the generation of antiviral immunity. Moreover, we provide novel insights how these receptors control both effector and memory T cell differentiation.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Células Precursoras de Linfocitos T/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Animales , Diferenciación Celular/inmunología , Supervivencia Celular/inmunología , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/prevención & control , Memoria Inmunológica/inmunología , Interleucina-15/inmunología , Interleucina-15/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Transducción de Señal/inmunologíaRESUMEN
Natural killer (NK) cells play an important role in the early defense against tumors and virally infected cells. Their function is thought to be controlled by the balance between activating and inhibitory receptors, which often compete for the same ligands. Several activating receptors expressed on virtually all NK cells lack an inhibitory partner, most notably CD16, NCR1 and NKG2D. We therefore hypothesized that a signal through at least one of these receptors is always required for full NK cell activation. We generated animals lacking all three receptors (TKO) and analyzed their NK cells. In vitro, TKO NK cells did not show reduced ability to kill tumor targets but displayed hyperresponsiveness to NK1.1 stimulation. In vivo, TKO animals had a minor reduction in their ability to control non-hematopoietic tumors and cytomegalovirus infection, which was the result of reduced NK cell activity. Together, our findings show that activating NK cell receptors without an inhibitory partner do not provide a 'master' signal but are integrated in the cumulative balance of activating and inhibitory signals. Their activity is controlled through regulation of the responsiveness and expression of other activating receptors. Our findings may be important for future development of NK cell-based cancer immunotherapy.
Asunto(s)
Subfamilia K de Receptores Similares a Lectina de Células NK , Neoplasias , Animales , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Células Asesinas Naturales/metabolismo , Receptores de Células Asesinas Naturales/metabolismo , Neoplasias/metabolismoRESUMEN
Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of nonalcoholic steatohepatitis (NASH), which can potentially lead to fibrosis and hepatocellular carcinoma, but the triggers of MAFLD-associated inflammation are not well understood. We have observed that lipid accumulation in hepatocytes induces expression of ligands specific to the activating immune receptor NKG2D. Tissue-resident innate-like T cells, most notably γδ T cells, are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit proinflammatory cells into the liver, which causes NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in dietary models of NASH and had a decreased incidence of hepatic tumors. The frequency of IL-17A+ γδ T cells in the blood of patients with MAFLD correlated directly with liver pathology. Our findings identify a key molecular mechanism through which stressed hepatocytes trigger inflammation in the context of MAFLD.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Humanos , Ratones , Hepatocitos/metabolismo , Hepatocitos/patología , Inflamación/patología , Interleucina-17/metabolismo , Cirrosis Hepática/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK , Linfocitos T/metabolismoRESUMEN
NKG2D is known as a potent activating receptor of the immune system. It is expressed on a multitude of immune cells, including NK cells and different subsets of T cells. NKG2D recognizes various MHC I-like ligands that are induced on target cells exposed to stressors such as viral infection, DNA damage and oncological transformation. NKG2D drives or facilitates cytotoxic and cytokine responses towards cells expressing its ligands to eliminate the threat. Therefore, NKG2D is usually classified as a sensor that translates cellular stress into activation signals for immune cells. However, more recently it has become evident that NKG2D plays a role beyond direct killing of target cells. Lack of NKG2D affects development of NK cells in the bone marrow, resulting in hyperreactive NK cells. NKG2D deficiency on CD8 T cells affects the ability of effector cells to produce cytokines in response to T cell receptor engagement and reduces their capacity to establish immunological memory. Although NKG2D is not expressed on B cells subsets, lack of this receptor in hematopoietic precursors affects B cell development. Homing of mature B2 cells is altered in NKG2D-deficient mice and they have a strong reduction in peripheral B1a cell numbers, resulting in increased susceptibility to bacterial infections. The exact molecular mechanisms via which NKG2D mediates these versatile functions is still being explored, but appears to depend on the control of activation thresholds, either in hematopoietic precursors or mature immune cell subsets. In this review, we will elaborate on the underappreciated developmental and regulatory roles of NKG2D.