Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1101525 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28724572_1.fastq.gz | Fastqsanger.gz | |||
| SRR28724572_2.fastq.gz | Fastqsanger.gz | |||
| SRR28724573_1.fastq.gz | Fastqsanger.gz | |||
| SRR28724573_2.fastq.gz | Fastqsanger.gz | |||
| SRR28724574_1.fastq.gz | Fastqsanger.gz |
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Project description:Through forward genetic screening, we found a gene called LDL receptor Related Protein 10 (Lrp10) that plays an important role in the homeostasis and differentiation of peripheral CD8 T cells through its effects on the interleukin 7 receptor (IL7R). Lrp10 knockout mice exhibit enhanced resistance to MC38 tumor growth, and we sought to better define the tumor infiltrating Lrp10+/+ and Lrp10-/- CD8T cells using single cell RNA seq and paired single cell TCR sequencing.
2024-04-26 | GSE264241 | GEO
Project description:Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T-cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T-cell function. Through forward genetic screening in mice, we discover that loss-of-function mutations in LDL receptor-related protein 10 (Lrp10) cause naive and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. T-cell activation induces Lrp10 expression, which post-translationally suppresses IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhances T-cell homeostatic expansion through IL7R signaling. Lrp10-deficient mice are also intrinsically resistant to syngeneic tumors. This phenotype depends on dense tumor infiltration of CD8 T cells, which display increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T-cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy.
| S-EPMC11315911 | biostudies-literature
Project description:Signals emanating from the T cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T cell function. Through forward genetic screening in mice, we discover that loss-of-function mutations in LDL receptor related protein 10 (Lrp10) causes naïve and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. T cell activation induces Lrp10 expression, which post-translationally suppresses IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhances T cell homeostatic expansion through IL7R signaling. Lrp10-deficient mice are also intrinsically resistant to syngeneic tumors. This phenotype depends on dense tumor infiltration of CD8 T cells, which display increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy.
| S-SCDT-10_1038-S44319-024-00191-W | biostudies-other
Project description:Genome-wide association studies in multiple sclerosis (MS) identified a polymorphism (rs6897932) located in the coding region of the alpha chain of the cytokine receptor interleukin 7 receptor (IL7R) as a component that increases susceptibility to develop the disease. This single nucleotide polymorphism (SNP) affects the splicing of the primary transcript leading to genotype-defined transcript ratios encoding either a full length membrane spanning form or a soluble receptor chain. Genotyping at the IL7R locus reveals that the region can be described by four haplotypes. Interestingly, only one out of three haplotypes harbouring the associated SNP is positively associated with MS whereas the other two do not show association. The minor allele containing haplotype shows a reduced susceptibility to develop MS. We hypothesized that additional functional or phenotypic differences exist between individuals homozygous for haplotypes shown to have either positive, negative, or neutral effect, on susceptibility to develop MS. Gene expression profiles of CD4+ T cells from MS individuals before and after stimulation with IL7 were recorded. Haplotype-specific gene signatures were found indicating small alterations in IL7/IL7R signal processing/sensitivity through JAK/STAT and p38/MAPK14. We can not exclude that the obtained signatures result from differences within the CD4+ T cell compartment that, in fact, should be seen as a consequence of systemic haplotype-specific processing of homeostatic and proliferation signals transmitted through IL7/IL7R. Samples of CD4+ cells were obtained from 7 MS patients (homozygous for Hap1 (3), Hap2 (2), Hap3 (2)). CD4+ cells were collected from peripheral blood, frozen and stored in liquid nitrogen. All samples were thawed and CD4+ cells were purified by magnetic bead separation. Purity and viability of cells was analyzed by Fluorescence Activated Cell Sorter (FACS). Total cellular RNA were extracted with TRIzol reagent and analyzed with the Human Gene 1.0 ST Array (affymetrix). IL7R haplotypes and susceptibility to develop MS: Hap1 homozygous <-> Risk <-> positive effect on MS susceptibility Hap2 homozygous <-> Hap2 <-> neutral effect on MS susceptibility Hap3 homozygous <-> Prot <-> neutral effect on MS susceptibility [Note: Haplotype nomenclature subject to revision.]
2015-04-14 | E-GEOD-37584 | biostudies-arrayexpress
Project description:Genome-wide association studies in multiple sclerosis (MS) identified a polymorphism (rs6897932) located in the coding region of the alpha chain of the cytokine receptor interleukin 7 receptor (IL7R) as a component that increases susceptibility to develop the disease. This single nucleotide polymorphism (SNP) affects the splicing of the primary transcript leading to genotype-defined transcript ratios encoding either a full length membrane spanning form or a soluble receptor chain. Genotyping at the IL7R locus reveals that the region can be described by four haplotypes. Interestingly, only one out of three haplotypes harbouring the associated SNP is positively associated with MS whereas the other two do not show association. The minor allele containing haplotype shows a reduced susceptibility to develop MS. We hypothesized that additional functional or phenotypic differences exist between individuals homozygous for haplotypes shown to have either positive, negative, or neutral effect, on susceptibility to develop MS. Gene expression profiles of CD4+ T cells from MS individuals before and after stimulation with IL7 were recorded. Haplotype-specific gene signatures were found indicating small alterations in IL7/IL7R signal processing/sensitivity through JAK/STAT and p38/MAPK14. We can not exclude that the obtained signatures result from differences within the CD4+ T cell compartment that, in fact, should be seen as a consequence of systemic haplotype-specific processing of homeostatic and proliferation signals transmitted through IL7/IL7R.
2015-04-14 | GSE37584 | GEO
Project description:IL-7-dependent STAT1 activation limits homeostatic CD4+ T cell expansion
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Project description:In order to find out taget genes of Runx/Cbfb2 complexes in PIR+IL7R+ subset. In particular, genes that would explain why the size of thymus was small by lack of Cbfb2. Upon finding of decresed IL7R+PIR+ subset, which was reported as thymus-homing progenitor, in Cbfb2 deficient embruos embryos, we focused on these population.
2017-12-05 | GSE86850 | GEO
Project description:IL-7 regulates homeostatic mechanisms that maintain the overall size of the T cell pool throughout life. We show that, under steady-state conditions, IL-7 signaling is principally mediated by activation of signal transducers and activators of transcription 5 (STAT5). In contrast, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in an IL-7-dependent STAT1 and STAT5 activation. Consequently, the IL-7-induced transcriptome is altered with enrichment of IFN-stimulated genes (ISGs). Moreover, STAT1 overexpression was associated with reduced survival in CD4+ T cells undergoing lymphopenia-induced proliferation (LIP). We propose a model in which T cells undergoing LIP upregulate STAT1 protein, "switching on" an alternate IL-7-dependent program. This mechanism could be a physiological process to regulate the expansion and size of the CD4+ T cell pool. During HIV infection, the virus could exploit this pathway, leading to the homeostatic dysregulation of the T cell pools observed in these patients.
2018-01-01 | GSE106575 | GEO
Project description:Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemia stage in which B-cell precursors display self-renewal ability, initiating precursor B-ALL that resembles PAX5 P80R or Ph-like human leukemia. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving both JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are novel treatment avenues for IL-7R-related cases. Our model, a unique resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.
2021-11-02 | PXD017147 | Pride
Project description:Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes.
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