Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae
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PROVIDER: PRJNA431787 | ENA |
REPOSITORIES: ENA
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Project description:Invariant natural killer T cells (iNKT cells) are activated by lipid antigens presented by CD1d, but the pathway leading to lipid antigen presentation remains incompletely characterized. Here we show a whole genome siRNA screen to elucidate the CD1d presentation pathway. A majority of gene knockdowns that diminish antigen presentation reduced formation of glycolipid-CD1d complexes on the cell surface, including members of the HOPS and ESCRT complexes, genes affecting cytoskeletal rearrangement, and ABC family transporters. We validated the role in vivo for the multidrug resistance protein 1 (Mrp1) in CD1d antigen presentation. Mrp1 deficiency reduces surface clustering of CD1d, which decreased iNKT cell activation. Infected Mrp1 knock out mice show decreased iNKT cell responses to antigens from Streptococcus pneumoniae and were associated with increased mortality. Our results highlight the unique cellular events involved in lipid antigen presentation and show how modification of this pathway can lead to lethal infection.
2018-09-14 | GSE109717 | GEO
Project description:Regulatory B cells (Breg) express high levels of CD1d that presents lipid antigens to invariant natural killer T (iNKT) cells. The function of CD1d in Breg biology and iNKT cell activity during inflammation remains unclear. Here we show, using chimeric mice, cell depletion and adoptive cell transfer, that CD1d-lipid presentation by Bregs induces iNKT cells to secret IFN-γ to contribute, partially, to the down-regulation of T helper (Th)1 and Th17 adaptive immune responses for ameliorating experimental arthritis. Mice lacking CD1d-expressing B cells develop exacerbated diseases compared to wild-type mice, and fail to respond to α-galactosylceramide treatment. Absence of lipid presentation by B cells causes altered activation of iNKT cells, with disruption of regulatory pathways including those involved in metabolism and cytokine responses. Thus, we identify an IL-10-independent mechanism by which Bregs restrain excessive inflammation via lipid presentation.
2018-01-25 | E-MTAB-6381 | biostudies-arrayexpress
Project description:Invariant natural killer T (iNKT) cells are a group of innate like T cells that plays important roles in immune homeostasis and activation. We found that iNKT cells, compared to CD4+ T cells, have significantly higher levels of lipid peroxidation in both mice and humans. Proteomic analysis also demonstrated that iNKT cells express higher levels of Glutathione peroxidase 4 (Gpx4), a major antioxidant enzyme that reduces lipid peroxidation and prevents ferroptosis. T cell specific deletion of Gpx4 reduces iNKT cell population, most prominently the IFNg producing NKT1 subset. RNAseq analysis revealed IFNg signaling, cell cycle regulation, as well as mitochondrial function are perturbed by Gpx4 deletion in iNKT cells. Consistently, we detected impaired cytokine production, elevated cell proliferation and cell death, and accumulation of lipid peroxides and mitochondrial ROS in Gpx4 KO iNKT cells. Ferroptosis inhibitor, iron chelator, vitamin E and vitamin K2 can prevent ferroptosis induced by Gpx4 deficiency in iNKT cells and ameliorate the impaired function of iNKT cells due to Gpx4 inhibition. Lastly, vitamin E rescued iNKT cell population in Gpx4 KO mice. Altogether, our findings reveal the critical role of Gpx4 in regulating iNKT cell homeostasis and function, through controlling lipid peroxidation and ferroptosis.
2024-08-20 | GSE270485 | GEO
Project description:Invariant natural killer T cells (iNKT cells) are activated by lipid antigens presented by CD1d, but the pathway leading to lipid antigen presentation remains incompletely characterized. Here we show a whole-genome siRNA screen to elucidate the CD1d presentation pathway. A majority of gene knockdowns that diminish antigen presentation reduced formation of glycolipid-CD1d complexes on the cell surface, including members of the HOPS and ESCRT complexes, genes affecting cytoskeletal rearrangement, and ABC family transporters. We validated the role in vivo for the multidrug resistance protein 1 (Mrp1) in CD1d antigen presentation. Mrp1 deficiency reduces surface clustering of CD1d, which decreased iNKT cell activation. Infected Mrp1 knockout mice show decreased iNKT cell responses to antigens from Streptococcus pneumoniae and were associated with increased mortality. Our results highlight the unique cellular events involved in lipid antigen presentation and show how modification of this pathway can lead to lethal infection.
| S-EPMC6189046 | biostudies-literature
Project description:The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident lymphocytes, including lipid-reactive invariant natural killer T (iNKT) cells. iNKT cells have unique properties according to their tissues of residency, but if and how the tissue environment shapes their antigen specificity remains unknown. By analysing iNKT cells from tissues of mice and humans we demonstrate that their T cell receptor (TCR) repertoire is highly diverse and is distinct for iNKT cells resident in individual tissues resulting in differential lipid-antigen recognition. Within peripheral tissues, the TCR repertoire of iNKT cell recent thymic emigrants is different from that of mature cells, indicating that the iNKT population is shaped after their arrival to the tissues. Accordingly, in homeostatic conditions the repertoire of iNKT cells is modulated by tissue-specific signals that control iNKT cell activation and proliferation resulting in differential clonal expansion found for cells resident in various organs. Moreover, the iNKT cell TCR repertoire changes in response to lipid immunization and is shaped by age and by environmental changes. Thus, post-thymic modification of the iNKT cell TCR repertoire underpins the distinct antigen specificity of iNKT cells residing in peripheral tissues
2019-12-17 | GSE131420 | GEO
Project description:Invariant natural killer T (iNKT) cells are a specific innate-like counterpart of T lymphocytes, which response to lipid-based antigens and provide a functional bridge between the innate and adaptive immunity. The physiological role of m6A modification involved in NK cells differentiation remains unclear. We found that N6-Methyladenosine (m6A) methyltransferase METTL3 is intrinsically required for iNKT cell development and function in an m6A-dependent manner. To investigate the molecular mechanisms, m6A-LACE-seq was performed using iNKT cells and Merip-seq was performed using DP cells in thymocytes isolated from WT and KO mice to investigate the regulatory network.
2023-12-31 | GSE210325 | GEO
Project description:Invariant natural killer T (iNKT) cells are a specific innate-like counterpart of T lymphocytes, which response to lipid-based antigens and provide a functional bridge between the innate and adaptive immunity. The physiological role of m6A modification involved in NK cells differentiation remains unclear. We found that N6-Methyladenosine (m6A) methyltransferase METTL3 is intrinsically required for iNKT cell development and function in an m6A-dependent manner. To investigate the molecular mechanisms, RNA-seq was performed using iNKT cells in thymocytes isolated from WT and KO mice to investigate the regulatory network.
2023-12-31 | GSE210324 | GEO
Project description:Transcriptional profiling of iNKT gene expression in Map3k1 control and mutant mice
2016-06-01 | E-MTAB-1561 | biostudies-arrayexpress
Project description:Invariant natural killer T (iNKT) cells mediate immune responses when stimulated by glycolipid agonists presented by CD1d. In extensive studies of synthetic analogues of α-galactosyl ceramides, we identified numerous examples of significant differences in the recognition of specific glycolipids in wild type mice versus human iNKT cell clones or PBMC samples. To predict human iNKT cell responses more accurately in a mouse model, we derived a mouse line in which compound genetic modifications were used to express a human-like iNKT cell TCR along with human CD1d in place of the endogenous mouse proteins. Detailed transcriptional and phenotypic profiling demonstrated that these partially humanized mice developed an expanded population of T cells recognizing CD1d-presented glycolipid antigens, among which a subset characterized by expression of chemokine receptor CXCR6 had features characteristic of authentic iNKT cells. Responses to iNKT cell activating glycolipids in these mice generated cytokine production in vitro and in vivo that showed a pattern of fine specificity that closely resembled that of cultured human iNKT cell clones. Anti-tumor responses to variants of α‑galactosyl ceramide in VαKI mice also correlated with their potency for stimulating human iNKT cells. This genetically modified mouse line provides a practical model for human presentation and recognition of iNKT cell activators in the context of a normally functioning immune system, and may furnish valuable opportunities for preclinical evaluation of iNKT cell-based therapies.
2022-09-25 | GSE213954 | GEO
Project description:CD1d expression by thymocytes is required to select iNKT cells. When CD1d is expressed only on thymocytes (pLck-CD1d tg mice), iNKT cells are hyperresponsive to antigen stimulation suggesting that, in physiological conditions, these cells undergo functional education mediated by additional CD1d-expressing cells. Here, we investigated the mechanisms of this functional education. We find that peripheral iNKT cells from pLck-CD1d tg mice express significantly less SHP-1, a tyrosine phosphatase negatively regulating TCR signaling, than WT cells. iNKT cells from heterozygous SHP-1-mutated motheaten mice, displaying similar SHP-1 reduction as pLck-CD1d tg iNKT cells, are antigen-hyperresponsive. Restoring normal CD1d expression in pLck-CD1d tg mice normalizes SHP-1 expression and responsiveness of iNKT cells. In WT mice, iNKT cells upregulate SHP-1 and decrease responsiveness upon emigration from thymus to periphery. This depends on contacts with CD1d-expressing DCs. iNKT cell functional education is therefore controlled by DCs via tuning SHP-1 expression level in the periphery. Hepatic iNKT cells from wild-type and transgenic mice (expressing hCD1d molecule under the pLck promoter)
2013-03-01 | E-GEOD-42835 | biostudies-arrayexpress