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Principal Investigator: WEIGUO CUI
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $400,000
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
T cell exhaustion is a differentiation state that is marked by the loss of effector function and increased
expression of inhibitory receptors such as PD-1. Although virus-specific CD8 T cells are commonly considered
as a homogeneous population that gradually become exhausted over time, recent research has clearly
demonstrated that a CXCR5hi TCF-1hi subset is serving as a self-renewing progenitor population that can give
rise to a more terminally exhausted CXCR5lo TCF-1lo subset. To better dissect the heterogeneity of “exhausted”
CD8 T cells, the lab applied single cell RNA-seq (scRNA-seq) to the chronic LCMV infection and identified
three major subsets of virus-specific CD8 T cells that are phenotypically, functionally and transcriptionally
distinct. Not only had the lab validated the existence of these subsets of T cells experimentally by flow
cytometry, more advanced computational analyses were also performed to further predict their core
transcriptional networks and developmental trajectories. Collectively, the findings reveal that a TCF-1hi
progenitor subset can give rise to either a truly exhausted PD-1hi subset or a newly identified functional effector
population that is named CX3CR1hi subset. This discovery laid a solid framework that allows testing of how
extracellular signals and intrinsic genetic circuits regulate the formation and function of these three subsets of
CD8 T cells. More importantly, it provides unprecedented opportunities to explore the possibility of generating
more functional CX3CR1hi cells from TCF-1hi progenitors to overcome T cell exhaustion. This conceptual
breakthrough is obviously applicable to control over chronic viral infection as well as cancer. Intriguingly, the
preliminary study has also demonstrated that CD4 helper T cells, possibly through producing IL-21, are critical
for TCF-1hi CX3CR1hi transition. This led to the hypothesis that inflammatory cytokines (such as CD4-
derived IL-21) modulate the cellular, functional and transcriptional diversity of virus-specific CD8 T cells during
chronic LCMV infection. Blocking antibodies, RNA interference and genetic deletion models will be used to
further dissect how inflammatory cytokines and transcriptional networks regulate heterogeneity in T cell
exhaustion. Furthermore, the lab proposes to redirect CD8 T cell differentiation away from “exhaustion” by
providing additional “CD4 help”, either alone or in combination with PD-1 blockade. The lab will test if providing
IL-21 producing CD4 T cells through adoptive transfer could drive TCF-1hi progenitor cell differentiation into
functional CX3CR1hi effector cells. Overall, knowledge gained from this research will provide mechanistic
insights into how to redirect the formation of functional effector T cells and simultaneously limit T cell
exhaustion for improved viral control over chronic infection.
Terms: <ATAC sequencing><ATAC-seq><ATACseq><Acetylation><Adoptive Transfer><Affect><Antigens><Assay for Transposase-Accessible Chromatin using sequencing><Binding><Blocking Antibodies><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CSIF><CSIF-10><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chromatin><Chronic><Computer Analysis><Cytokine Signal Transduction><Cytokine Signaling><Cytokine Synthesis Inhibitory Factor><Development><Effector Cell><Enhancers><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Gene Transcription><Genetic><Genetic Transcription><Goals><Heterogeneity><IFN><IL-10><IL10><IL10A><IL21><Individual><Infection><Inflammatory><Interferons><Interleukin 10 Precursor><Interleukin-10><Intracellular Communication and Signaling><Knowledge><LCM Viruses><LCMV><Lymphocytic choriomeningitis virus><Malignant Neoplasms><Malignant Tumor><Mediating><Modeling><Molecular><Molecular Interaction><Names><PD 1><PD-1><PD-1 blockade><PD1><PD1 blockade><Pathway interactions><Phenotype><Population><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Process><RNA Expression><RNA Interference><RNA Silencing><RNAi><Receptor Protein><Research><Sequence-Specific Posttranscriptional Gene Silencing><Signal Transduction><Signal Transduction Systems><Signaling><Site><Solid><Surface><T cell differentiation><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Teff cell><Testing><Therapeutic><Time><Transcription><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Physiology><Virus><Virus Diseases><acute infection><anti-PD-1 blockade><anti-PD1 blockade><anti-cancer immunotherapy><anti-viral immunity><anticancer immunotherapy><antiviral immunity><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><biological signal transduction><cancer immunotherapy><chronic infection><computational analyses><computational analysis><computer analyses><cytokine><design><designing><developmental><effector T cell><epigenetically><exhaust><exhaustion><extracellular><flow cytophotometry><gene regulatory network><immune-based cancer therapies><immunogen><immunotherapy for cancer><immunotherapy of cancer><improved><insight><interleukin-21><malignancy><name><named><naming><neoplasm/cancer><pathway><persistent infection><progenitor><progenitor cell differentiation><progenitor cell population><progenitor differentiation><progenitor population><programmed cell death 1><programmed cell death protein 1><programmed death 1><receptor><response><scRNA-seq><self-renew><self-renewal><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><stem and progenitor cell population><stem and progenitor differentiation><stem cell differentiation><stem cell population><success><synergism><systemic lupus erythematosus susceptibility 2><thymus derived lymphocyte><viral infection><virus infection><virus-induced disease>