Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A humanized mouse model for in vivo evaluation of iNKT cell responses

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE213954 | GEO | 2022/09/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae

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

CD1d-dependent immune suppression mediated by regulatory B cells through modulations of iNKT cells

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

Expression data of hepatic iNKT cells from pLck-hCD1d transgenic mice

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

CD1d-restricted NKT cell function prevents insulin resistance in lean mice, and is regulated by adipocytes and is regulated by adipocytes

Project description:Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell–deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue–resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue–resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance. four samples

2012-08-06 | E-GEOD-39534 | biostudies-arrayexpress

Microarray screening of RNA samples from two human myeloma and two human lymphoma cell lines

Project description:This laboratory studies the T cell recognition of glycolipid antigens, including the biochemical characterization of glycolipid antigens, the cell biology of glycolipid antigen presenting machinery, the chemical synthesis of self and foreign glycolipids, and the cellular immunology that might shed light on finding glycolipid targets for adjuvant and vaccine development. In myeloid patients, the suppression of NKT cells has been reported. This suppression is mediated by endogenous glycolipid antigens presented by CD1d, a non-classic MHC molecule. Tumor B cells express CD1d molecule and preserve the capacity in presenting glycolipid antigens to NKT cells. However, the identity of the tumor glycolipid antigens remain unknown. We recently identified isoglobotrihexosylceramide (iGb3), as one endogenous ligand for human NKT cells. We have also purified iGb3 from thymuses of pediatric patients. Thus we hypothesize that iGb3 might be directly linked to the NKT suppression in myeloma patients. The processing of iGb3 requires the “assembly line” of glycosyltransferases, the glycosidases and sphingolipid activator proteins. The loading of iGb3 antigen is dependent on lipid transfer proteins such as saposins, and the more recently characterized CD1e molecule. Thus we used the Glyo-chip approach to have a systemic survey of the above enzyme and protein components. We hope to find clues to help us in understanding the glycolipid antigen presentation in tumor B cells. EXPERIMENT: We purified RNA from 2 myeloma cell lines (U226 and 8226) by the RNAqueous kit from Ambion, TX. RNA was also purified from 2 lymphoma cell lines (Daudi and RL). 4 samples were provided to Core E of Consortium of Functional Genomics for Glyco-chip version 2 array.

2011-03-02 | E-GEOD-27600 | biostudies-arrayexpress

Liver iNKT transcriptional profiling

Project description:Invariant NKT (iNKT) cells comprise a heterogeneous group of terminally differentiated, non-circulating, tissue-resident T-lymphocytes that recognize glycolipids, including alpha-galactosylceramide (aGalCer), in the context of CD1d. Here, we show that murine and human liver-resident aGalCer/CD1d-binding iNKTs correspond to a novel Zbtb16+/Tbx21+/Gata3+/Maflow/Rorc– subset that exhibits profound plasticity. Repetitive encounters of these cells with intravenously-delivered aGalCer/CD1d-coated nanoparticles (NPs) trigger their differentiation into immunoregulatory, IL-10/IL-21-producing, Mafhigh cells expressing a T-regulatory type 1 (TR1)-like transcriptional signature.

2022-04-22 | GSE168488 | GEO

Expression data of hepatic iNKT cells from pLck-hCD1d transgenic mice

2013-03-01 | GSE42835 | GEO

Microarray screening of RNA samples from two human myeloma and two human lymphoma cell lines

2011-03-02 | GSE27600 | GEO

Immunological Proteome Resource (ImmPRes): Liver derived CD4+ T cell proteomes

Project description:T cells play a critical role in liver immunity and take part both in the initiation and in the resolution of intrahepatic inflammation. The liver contains conventional CD4 T cells, and Natural Killer T (NKT) cells that express an invariant Vα14 T cell receptor that recognizes glycolipid/CD1d antigen complexes (iNKTs) and play a role in immune surveillance and immune homeostasis. ImmPRes includes a TMT based dataset characterising the proteomes of ex-vivo liver derived CD4+ T cells along with invariant NKT (iNKT) cells

2022-08-26 | PXD036319 | Pride

CD1d-restricted NKT cell function prevents insulin resistance in lean mice, and is regulated by adipocytes and is regulated by adipocytes

2012-08-07 | GSE39534 | GEO