Osteopontin regulates development and function of invariant natural killer T cells.
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ABSTRACT:
SUBMITTER: Diao H
PROVIDER: S-EPMC2560993 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Natural killer (NK) cells play an essential role in the immune response to infection and cancer. After infection or during homeostatic expansion NK cells express a developmental program that includes a contraction phase followed by the formation of long-lived mature memory-like cells. Although this NK cell response pattern is well established, the underlying mechanisms that ensure efficient transition to long-lived NK cells remain largely undefined. Here we report that deficient expression of intracellular osteopontin (OPN-i) by NK cells results in defective responses to IL-15 associated with a substantial increase in the NK cell contraction phase of homeostatic expansion, defective expression of the Eomes transcription factor, and diminished responses to metastatic tumors. The OPN-i-deficient phenotype is accompanied by increased NK cell apoptosis, impaired transition from immature to mature NK cells, and diminished ability to develop memory-like NK cells that respond to mouse cytomegalovirus. Gene pathway analysis of OPN-i-deficient NK cells suggests that the mechanistic target of rapamycin pathway may connect OPN-i to Eomes and T-bet expression by mature NK cells following up-regulation of OPN-i after IL-15 stimulation. Identification of OPN-i as an essential molecular component for maintenance of functional NK cell expansion provides insight into the NK cell response and may provide the basis for improved approaches to immunotherapy for infectious disease and cancer.
| S-EPMC4299239 | biostudies-literature
Project description:While the invariant natural killer T (iNKT)-cell response to primary stimulation with the glycolipid, ?-galactosylceramide (?GalCer), is robust, the secondary response to this stimulus is muted resulting in a hyporesponsive state characterized by anti-inflammatory interleukin-10 (IL-10) production and high expression of programmed cell death 1 (PD1) and neuropilin 1 (NRP1). The E protein transcription factors and their negative regulators, the Id proteins, have previously been shown to regulate iNKT cell thymic development, subset differentiation and peripheral survival. Here, we provide evidence that the expression of the transcriptional regulator Id2 is downregulated upon stimulation of iNKT cells with their cognate antigen. Moreover, loss of Id2 expression by iNKT cells resulted in a hyporesponsive state, with splenic Id2-deficient iNKT cells expressing low levels of TBET, high levels of PD1 and NRP1 and production of IL-10 upon stimulation. We propose that downregulation of Id2 expression is an essential component of induction of the anti-inflammatory, hyporesponsive state in iNKT cells.
| S-EPMC4980213 | biostudies-other
Project description:Conventional T cell fate and function are determined by coordination between cellular signaling and mitochondrial metabolism. Invariant natural killer T (iNKT) cells are an important subset of "innate-like" T cells that exist in a preactivated effector state, and their dependence on mitochondrial metabolism has not been previously defined genetically or in vivo. Here, we show that mature iNKT cells have reduced mitochondrial respiratory reserve and iNKT cell development was highly sensitive to perturbation of mitochondrial function. Mice with T cell-specific ablation of Rieske iron-sulfur protein (RISP; T-Uqcrfs1-/- ), an essential subunit of mitochondrial complex III, had a dramatic reduction of iNKT cells in the thymus and periphery, but no significant perturbation on the development of conventional T cells. The impaired development observed in T-Uqcrfs1-/- mice stems from a cell-autonomous defect in iNKT cells, resulting in a differentiation block at the early stages of iNKT cell development. Residual iNKT cells in T-Uqcrfs1-/- mice displayed increased apoptosis but retained the ability to proliferate in vivo, suggesting that their bioenergetic and biosynthetic demands were not compromised. However, they exhibited reduced expression of activation markers, decreased T cell receptor (TCR) signaling and impaired responses to TCR and interleukin-15 stimulation. Furthermore, knocking down RISP in mature iNKT cells diminished their cytokine production, correlating with reduced NFATc2 activity. Collectively, our data provide evidence for a critical role of mitochondrial metabolism in iNKT cell development and activation outside of its traditional role in supporting cellular bioenergetic demands.
| S-EPMC8020658 | biostudies-literature
Project description:Invariant natural killer T (iNKT) cells represent a unique population of CD1d-restricted T lymphocytes expressing an invariant T cell receptor encoded by V?14-J?18 and V?24-J?18 gene segments in mice and humans, respectively. Recognition of CD1d-loaded endogenous lipid antigen(s) on CD4/CD8-double positive (DP) thymocytes is essential for the development of iNKT cells. The lipid repertoire of DP thymocytes and the identity of the decisive endogenous lipid ligands have not yet been fully elucidated. Glycosphingolipids (GSL) were implicated to serve as endogenous ligands. However, further in vivo investigations were hampered by early embryonal lethality of mice deficient for the key GSL-synthesizing enzyme glucosylceramide (GlcCer) synthase [GlcCer synthase (GCS), EC 2.4.1.80]. We have now analyzed the GSL composition of DP thymocytes and shown that GlcCer represented the sole neutral GSL and the acidic fraction was composed of gangliosides. Furthermore, we report on a mouse model that by combination of Vav-promoter-driven iCre and floxed GCS alleles (Vav Cre GCS f/f ) enabled an efficient depletion of GCS-derived GSL very early in the T cell development, reaching a reduction by 99.6% in DP thymocytes. Although the general T cell population remained unaffected by this depletion, iNKT cells were reduced by approximately 50% in thymus, spleen, and liver and showed a reduced proliferation and an increased apoptosis rate. The V?-chains repertoire and development of iNKT cells remained unaltered. The GSL-depletion neither interfered with expression of CD1d, SLAM, and Ly108 molecules nor impeded the antigen presentation on DP thymocytes. These results indicate that GlcCer-derived GSL, in particular GlcCer, contribute to the homeostatic development of iNKT cells.
| S-EPMC5519558 | biostudies-literature
Project description:After activation, some invariant natural killer T (iNKT) cells are differentiated into Klrg1+ long-lived effector NKT1 cells. However, the regulation from the effector phase to the memory phase has not been elucidated. Zeb2 is a zinc finger E homeobox-binding transcription factor and is expressed in a variety of immune cells, but its function in iNKT cell differentiation remains also unknown. Here, we show that Zeb2 is dispensable for development of iNKT cells in the thymus and their maintenance in steady state peripheral tissues. After ligand stimulation, Zeb2 plays essential roles in the differentiation to and maintenance of Klrg1+ Cx3cr1+GzmA+ iNKT cell population derived from the NKT1 subset. Our results including single-cell-RNA-seq analysis indicate that Zeb2 regulates Klrg1+ long-lived iNKT cell differentiation by preventing apoptosis. Collectively, this study reveals the crucial transcriptional regulation by Zeb2 in establishment of the memory iNKT phase through driving differentiation of Klrg1+ Cx3cr1+GzmA+ iNKT population.
| S-EPMC10616117 | biostudies-literature
Project description:There is heterogeneity in invariant natural killer T (iNKT) cells based on the expression of CD4 and the IL-17 receptor B (IL-17RB), a receptor for IL-25 which is a key factor in T(H)2 immunity. However, the development pathway and precise function of these iNKT cell subtypes remain unknown. IL-17RB?iNKT cells are present in the thymic CD44?/? NK1.1? population and develop normally even in the absence of IL-15, which is required for maturation and homeostasis of IL-17RB?iNKT cells producing IFN-?. These results suggest that iNKT cells contain at least two subtypes, IL-17RB? and IL-17RB? subsets. The IL-17RB?iNKT subtypes can be further divided into two subtypes on the basis of CD4 expression both in the thymus and in the periphery. CD4? IL-17RB?iNKT cells produce T(H)2 (IL-13), T(H)9 (IL-9 and IL-10), and T(H)17 (IL-17A and IL-22) cytokines in response to IL-25 in an E4BP4-dependent fashion, whereas CD4? IL-17RB?iNKT cells are a retinoic acid receptor-related orphan receptor (ROR)?t? subset producing T(H)17 cytokines upon stimulation with IL-23 in an E4BP4-independent fashion. These IL-17RB?iNKT cell subtypes are abundantly present in the lung in the steady state and mediate the pathogenesis in virus-induced airway hyperreactivity (AHR). In this study we demonstrated that the IL-17RB?iNKT cell subsets develop distinct from classical iNKT cell developmental stages in the thymus and play important roles in the pathogenesis of airway diseases.
| S-EPMC3274505 | biostudies-literature
Project description:Invariant natural killer T (iNKT)-cell development is controlled by many polymorphic genes present in commonly used mouse inbred strains. Development of type 1 diabetes (T1D) in NOD mice partly results from their production of fewer iNKT-cells compared with non-autoimmune-prone control strains, including ICR. We previously identified several iNKT-cell quantitative trait genetic loci co-localized with known mouse and human T1D regions in a (NOD × ICR)F2 cross. To further dissect the mechanisms underlying the impaired iNKT-cell compartment in NOD mice, we carried out a series of bone marrow transplantation as well as additional genetic mapping studies. We found that impaired iNKT-cell development in NOD mice was mainly due to the inability of their double-positive (DP) thymocytes to efficiently select this T-cell population. Interestingly, we observed higher levels of CD1d expression by NOD than by ICR DP thymocytes. The genetic control of the inverse relationship between the CD1d expression level on DP thymocytes and the frequency of thymic iNKT-cells was further mapped to a region on chromosome 13 between 60.12 and 70.59 Mb. The NOD allele was found to promote CD1d expression and suppress iNKT-cell development. Our results indicate that genetically controlled physiological variation of CD1d expression levels modulates iNKT-cell development.
| S-EPMC4409484 | biostudies-literature
Project description:Natural killer T-cells, with an invariant T-cell antigen receptor ?-chain (iNKT cells), are unique and conserved subset of lymphocytes capable of altering the immune system through their rapid and potent cytokine responses. They are reactive to lipid antigens presented by the CD1d molecule, an antigen-presenting molecule that is not highly polymorphic. iNKT cell responses frequently involve mixtures of cytokines that work against each other, and therefore attempts are underway to develop synthetic antigens that elicit only strong interferon-gamma (IFN?) or only strong interleukin-4 responses but not both. Strong IFN? responses may correlate with tighter binding to CD1d and prolonged stimulation of iNKT cells, and this may be useful for vaccine adjuvants and for stimulating anti-tumor responses. iNKT cells are self-reactive although the structure of the endogenous antigen is controversial. By contrast, bacterial and fungal lipids that engage the T-cell receptor and activate IFN? from iNKT cells have been identified from both pathogenic and commensal organisms and the responses are in some cases highly protective from pathogens in mice. It is possible that the expanding knowledge of iNKT cell antigens and iNKT cell activation will provide the basis for therapies for patients suffering from infectious and immune diseases and cancer.
| S-EPMC6138764 | biostudies-literature
Project description:Conventional T cell fate and function are determined by coordination between cellular signaling and metabolism. Invariant natural killer T (iNKT) cells are a subset of “innate-like” pre-activated T cells whose dependence on mitochondrial metabolism remains elusive. Here, we showed that mature iNKT cells have reduced mitochondrial respiratory reserve and iNKT cell development was highly sensitive to perturbation of mitochondrial function. Mice with T cell-specific ablation of Rieske Iron-Sulphur protein (T-Uqcrfs1-/-), an essential subunit of mitochondrial complex III, had a dramatic reduction of iNKT cells in the thymus and periphery, but minimal effects on conventional T cell development. Residual iNKT cells in T-Uqcrfs1-/- mice retained ability to proliferate but exhibited increased apoptosis, decreased TCR signaling and impaired responses to TCR and IL-15 stimulation. Furthermore, knocking down RISP in mature iNKT cells diminished their cytokine production, correlating with reduced NFATC2 activity. Collectively, our data demonstrate a critical role for mitochondrial metabolism in iNKT cell development and activation outside of supporting bioenergetic demands.
2021-03-12 | GSE157283 | GEO
Project description:BackgroundThe failure of immune surveillance to remove senescent cells drive age-related diseases. Here, we target an endogenous immune surveillance mechanism that can promote elimination of senescent cells and reverse disease progression.MethodsWe identify a class of lipid-activated T cells, invariant natural killer T cells (iNKTs) are involved in the removal of pathologic senescent cells. We use two disease models in which senescent cells accumulate to test whether activation of iNKT cells was sufficient to eliminate senescent cells in vivo.FindingsSenescent preadipocytes accumulate in white adipose tissue of chronic high-fat diet (HFD) fed mice, and activation of iNKT cells with the prototypical glycolipid antigen alpha-galactosylceramide (αGalCer) led to a reduction of these cells with improved glucose control. Similarly, senescent cells accumulate within the lungs of mice injured by inhalational bleomycin, and αGalCer-induced activation of iNKT cells greatly limited this accumulation, decreased the lung fibrosis and improved survival. Furthermore, co-culture experiments showed that the preferential cytotoxic activity of iNKT cells to senescent cells is conserved in human cells.ConclusionsThese results uncover a senolytic capacity of tissue-resident iNKT cells and pave the way for anti-senescence therapies that target these cells and their mechanism of activation.
| S-EPMC8491998 | biostudies-literature