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Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3

ABSTRACT: Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3

PROVIDER: PRJNA819445 | ENA |

REPOSITORIES: ENA

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			Action	DRS
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	SRR18471539_1.fastq.gz	Fastqsanger.gz
	SRR18471539_2.fastq.gz	Fastqsanger.gz
	SRR18471540_1.fastq.gz	Fastqsanger.gz
	SRR18471540_2.fastq.gz	Fastqsanger.gz

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Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3

Project description:CD8+ T cell exhaustion is a distinct differentation state resulting from chronic antigen exposure and leading to hierarchical loss of effector functions. Using a murine model of diabetes, we show that CD8+ T cells derived from the islets of diabetic mice have CD8+ T cells that are canonically exhausted and yet retain sufficient effector function to contribute to pathogenicity in autoimmune diabetes. Genetic deletion of the inhibitory receptor LAG3 restricted to only CD8+ T cells lead to accelerated disease, with LAG3 deficient CD8+ T cells having enhanced effector function and trafficking. These findings reveal a distinct role of LAG3 in restraining autoreactive CD8+ T cells and implicate LAG3 as a potential therapeutic target in autoimmunity.

2022-04-08 | GSE199357 | GEO

LAG3 and PD1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN gamma-dependent anti-tumor immunity

Project description:Combined nivolumab (anti-PD1) and relatlimab (anti-LAG3) have shown enhanced effectiveness in melanoma patients. However, how these two receptors work together to hinder anti-tumor immunity remains unclear. Our study demonstrates that PD1/LAG3-deficient CD8+ T cells with more effectively clearing tumors and survive longer in melanoma mouse models. These PD1/LAG3-deficient CD8+ T cells have unique transcriptional profiles, broad TCR clonality, and enriched effector-like and interferon-responsive genes, leading to increased IFN gamma release indicating functionality. PD1 and LAG3 together drive T cell exhaustion, with a significant impact on TOX modulation. Mechanistically, autocrine IFN gamma signaling is crucial for enhancing anti-tumor immunity in PD1/LAG3-deficient CD8+ T cells, providing insights into the enhanced efficacy of combined PD1 and LAG3 targeting.

2024-08-07 | GSE262740 | GEO

Single-cell analysis predicts that mesenchymal ovarian cancer cells promote CD8+ T cell exhaustion through the LGALS3 - LAG3 axis

Project description:Cancer cells often metastasize by undergoing an epithelial-mesenchymal transition (EMT). Although abundance of CD8+ T-cells in the tumor microenvironment correlates with improved survival, mesenchymal cancer cells acquire greater resistance to antitumor immunity in some cancers. We hypothesized the EMT modulates the immune response to ovarian cancer. Here we show that cancer cells from infiltrated/inflamed tumors possess more mesenchymal cells, than excluded and desert tumors. We also noted high expression of LGALS3 is associated with EMT in vivo, a finding validated with in vitro EMT models. Dissecting the cellular communications among populations in the tumor revealed that mesenchymal cancer cells in infiltrated tumors communicate through LGALS3 to LAG3 receptor expressed by CD8+ T cells. We found CD8+ T cells express high levels of LAG3, a marker of T cell exhaustion. The results indicate that EMT in ovarian cancer cells promotes interactions between cancer cells and T cells through the LGALS3 - LAG3 axis, which could increase T cell exhaustion in infiltrated tumors, dampening antitumor immunity.

2023-11-07 | GSE247098 | GEO

Transcription profiling of mouse CD4+ CD25+, CD4+ CD25- CD45RBlow LAG3+ and CD4+ CD25- CD45RBlow LAG3- T cells

Project description:Comparison of gene expression profile of CD4+ CD25+, CD4+ CD25- CD45RBlow LAG3+ and CD4+ CD25- CD45RBlow LAG3- T cells. Naive CD4+CD25-CD45RBhigh T cells were used as a reference for pair comparison with values from the three other subsets.

2009-08-19 | E-MEXP-1343 | biostudies-arrayexpress

Murine bone marrow immature B cells: autoreactive versus non-autoreactive

Project description:Transcriptional profiling of mouse bone marrow B220+CD23–CD43–IgD– autoreactive immature B cells from 3-83Igi,Rag1-/-,H-2b mice relative to non-autoreactive immature B cells from 3-83Igi,H-2d mice. Goal was to determine genes that potentially mediate negative and positive selection of immature B cells. Biological replicates: 2 autoreactive replicate against, 2 non-autoreactive replicates

2010-08-31 | E-GEOD-22802 | biostudies-arrayexpress

Transcrpition landscapes of CD4 T cell exhaustion in response to transplant antigen

Project description:We report the gene profiles of exhaustion-like and effector-like CD4 T cells in response to transplant antigen. To obain the transcprition landscapes of exhuasted and effector CD4 T cells , we generated RNA-seq of TCR transgeneic TEa cells in response to abundant IE-α antigen (exhuast) or to Balb/c skin grafts (effector). We find that TEa cells upregulated the expression level of key exhaustion genes, including Pdcd1, Tox, lag3, Cd38, Cd200, as well as downregulated the expression levels of effector genes Ifng, Gzmb, Prf1, Tbx21, Il2ra, Fasl and Klrg1. This study provides a better understanding of CD4 T cell exhaustion in response to alloantigen.

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Murine bone marrow immature B cells: autoreactive versus non-autoreactive

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Lymphocyte activation gene 3 (Lag3) supports Foxp3+ Treg cell function by restraining c-Myc-dependent aerobic glycolysis

Project description:Lymphocyte activation gene 3 (Lag3) has emerged as the next-generation immune checkpoint molecule due to its ability to inhibit effector T cell activity. Foxp3+ regulatory T (Treg) cells, a master regulator of immunity and tolerance, also highly express Lag3. While Lag3 is thought to be necessary for Treg cell-mediated regulation of immunity, the precise roles and underlying mechanisms remain largely elusive. In this study, we report that Lag3 is indispensable for Treg cells to control autoimmune inflammation. Utilizing a newly generated Treg cell specific Lag3 mutant mouse model, we found that these animals are highly susceptible to autoimmune diseases, suggesting defective Treg cell function. Genome wide transcriptome analysis further uncovered that Lag3 mutant Treg cells upregulated genes involved in metabolic processes. Mechanistically, we found that Lag3 limits Treg cell expression of Myc, a key regulator of aerobic glycolysis. We further found that Lag3-dependent Myc expression determines Treg cells’ metabolic programming as well as the in vivo function to suppress autoimmune inflammation. Taken together, our results uncovered a novel function of Lag3 in supporting Treg cell suppressive function by regulating Myc-dependent metabolic programming.

2024-08-30 | GSE226083 | GEO

Single-cell analysis predicts that mesenchymal ovarian cancer cells promote CD8+ T cell exhaustion through the LGALS3 - LAG3 axis

Project description:Single-cell analysis predicts that mesenchymal ovarian cancer cells promote CD8+ T cell exhaustion through the LGALS3 - LAG3 axis

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Transcriptional analysis of LAG3 deficient Tregs in an inflamed CNS

Project description:Transcriptonal analysis of Tregs reveal role of LAG3 in stability and function of Tregs in an inflamed CNS

2020-11-01 | GSE159342 | GEO