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Series GSE199357 Query DataSets for GSE199357
Status Public on Apr 08, 2022
Title Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary 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.
 
Overall design NOD mice harboring a CD8+ T cell restricted genetic deletion of LAG3 were used to assess the role of LAG3 in autoimmune diabetes and were compared to control mice. CD8+ T cells were isolated from islets and lymph nodes by FACS. Bulk RNAseq, single-cell RNAseq with paired TCRseq, and single-cell ATACseq were performed on these isolated CD8+ T cells from control and LAG3 deleted mice. CD8+ T cells from three eight-week old female mice per group were pooled across two independent experiments for bulk RNAseq. CD8+ T cells from four eight-week old mice per group were used for scRNAseq experiments. CD8+ T cells from four eight-week old mice were used for scATACseq experiments.
 
Contributor(s) Cillo AR, Grebinowski S, Vignali DA
Citation(s) 35618829
NIH grant(s)
Grant ID Grant title Affiliation Name
R01 DK089125 Parameters that Underlie Treg Insufficiency in Autoimmune Diabetes UNIVERSITY OF PITTSBURGH AT PITTSBURGH Dario AA Vignali
R01 AI144422 Structure, Function and Mechanistic Analysis of LAG3 UNIVERSITY OF PITTSBURGH AT PITTSBURGH Dario AA Vignali
R01 AI144422 Structure, Function and Mechanistic Analysis of LAG3 UNIVERSITY OF PITTSBURGH AT PITTSBURGH CREG J WORKMAN
P01 AI108545 Synergies among inhibitory receptors in tolerance, cancer & antiviral immunity UNIVERSITY OF PITTSBURGH AT PITTSBURGH Dario AA Vignali
F31 AI147638 Investigating a disintegrin and metalloproteinase-mediated Neuropilin 1 cleavage in autoimmune diabetes UNIVERSITY OF PITTSBURGH AT PITTSBURGH Stephanie Grebinoski
T32 AI089443 Autoimmunity and Immunopathology Training Program UNIVERSITY OF PITTSBURGH AT PITTSBURGH MARK J SHLOMCHIK
Submission date Mar 24, 2022
Last update date Jul 08, 2022
Contact name Anthony Richard Cillo
E-mail(s) arc85@pitt.edu
Organization name University of Pittsburgh
Department Immunology
Street address The Assembly, Room 4070C Bay 10, 5051 Centre Ave
City Pittsburgh
State/province PA
ZIP/Postal code 15213
Country USA
 
Platforms (2)
GPL21626 NextSeq 550 (Mus musculus)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (23)
GSM5970966 bulk_rnaseq_wt_ln_1
GSM5970967 bulk_rnaseq_wt_ln_2
GSM5970968 bulk_rnaseq_wt_islet_3
Relations
BioProject PRJNA819445

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE199357_RAW.tar 1.3 Gb (http)(custom) TAR (of BIGWIG, TAR, TXT)
GSE199357_diabetes_bulk_rnaseq_counts.txt.gz 974.8 Kb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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