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Principal Investigator: Surojit Sarkar
Organization: SEATTLE CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $645,958
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Quiescent TCF1Hi stem-like CD8 T cells – functionally poised to rapidly expand and mount a vigorous
anti-viral immune response – are critical for mediating effective viral control while avoiding immunopathology
during chronic viral infections. The phenotypic, functional and molecular features of TCF1Hi stem-like CD8 T cells
are well characterized. However, very little is known about the precise signals that drive their generation. The
overarching goals of this proposal are to (i) define how the long-term pool of TCF1Hi stem-like anti-viral CD8 T
cells is generated during chronic viral infections, and (ii) leverage this knowledge for devising strategies to
engineer conceptually novel checkpoint blockade and adoptive cell transfer therapies in situations where
viral/antigen persistence drives functional exhaustion and loss of host immunity.
This proposal is founded on newly published and unpublished findings from our team showing a critical
and unexpected role of tempered IL-2 signals in the development of TCF1Hi stem-like CD8 T cells during chronic
viral infection. Our preliminary studies further show that IL-2 production by virus-specific CD8 T cells is inversely
related to PD-1 signals during priming. Additionally, we and others have shown that loss of PD-1 signals leads
to metabolic dysregulation and impaired survival of antiviral CD8 T cells that are key to long-term viral control.
Collectively, these findings present a unique role of the PD-1/IL-2 nexus during early T cell priming, in
programming the development of TCF1Hi stem-like CD8 T cells, for long-term maintenance of host anti-viral
responses. We hypothesize that PD-1-driven regulation of IL-2 production during priming promotes the
development of stem-like quiescent CD8 T cells. We further propose that mechanisms that promote inhibitory
PD-1 signals and temper IL-2 signals to CD8 T cells, during early T cell priming and initiation of anti-viral host
immune responses, would lead to the generation of TCF1Hi stem-like CD8 T cells with enhanced potential for
functional rejuvenation and viral control in response to checkpoint blockade.
We will engage high dimensional single cell transcriptomic, metabolomic and proteomic tools along with
leading edge RNP-based in vivo Crispr/Cas9 technology and conditional gene ablation models to: (1) Dissect
the programming of TCF1Hi stem-like CD8 T cells during early stages of chronic viral infections through the PD-
1-driven IL-2 regulatory axis. (2) Explore novel preconditioning strategies to enhance TCF1Hi stem-like cells
during established chronic viral infections for improved PD-1 checkpoint blockade through g-chain cytokines. (3)
Establish the relationship between IL-2 signaling signatures and stem-like T cells, vis a vis clinical outcomes of
checkpoint blockade, for Polyoma virus-specific exhausted CD8 T cells in human patient samples.
Successful completion of these studies will provide fundamental insight into the ontogeny of stem-like
TCF1Hi cells, alongside translational advances into discovery of newer druggable targets for improved control of
chronic viral infections.
Terms: <AIDS Virus><Ablation><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Address><Adoptive Cell Transfers><Affinity><Agonist><Anti-viral Response><Antibodies><Antigens><Bypass><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancers><Cas nuclease technology><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell-Mediated Lympholytic Cells><Cells><Chronic><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Co-Stimulator><Coronaviridae><Coronavirus><Costimulator><Cutaneous Neuroendocrine Carcinoma><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Dengue><Development><Drug Therapy><Engineering><Epidermal Thymocyte Activating Factor><Event><Generalized Growth><Generations><Genes><Goals><Grippe><Growth><HBV><HBV infection><HCV><HIV><HIV Infections><HTLV-III Infections><HTLV-III-LAV Infections><Hepatitis B Infection><Hepatitis B Virus><Hepatitis C virus><Homologous Serum Hepatitis Virus><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><IL-2><IL2 Protein><Immune mediated therapy><Immune response><Immunity><Immunological response><Immunologically Directed Therapy><Immunotherapy><Impairment><Individual><Infection><Influenza><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intracellular Communication and Signaling><Knowledge><LAV-HTLV-III><LCM Viruses><LCMV><Lower Respiratory Tract Infection><Lower respiratory infection><Lymphadenopathy-Associated Virus><Lymphocyte Mitogenic Factor><Lymphocytic choriomeningitis virus><Maintenance><Malignant Neoplasms><Malignant Tumor><Mediating><Memory><Merkel Cell Tumor><Merkel cell cancer><Merkel cell carcinoma><Metabolic><Mitogenic Factor><Modeling><Modern Man><Molecular><Neuroendocrine Carcinoma of the Skin><Outcome><PD 1><PD-1><PD-1 antibody therapy><PD-1 therapy><PD1><PD1 antibody therapy><PD1 based treatment><Pathogenesis><Pathology><Patients><Pharmacotherapy><Phenotype><Polyoma><Polyoma Viruses><Polyomavirus><Population><Production><Property><Proteomics><Public Health><Publishing><Regimen><Regulation><Rejuvenation><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Sampling><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Signal Transduction><Signal Transduction Systems><Signaling><Source><T cell growth factor><T cell response><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T8 Cells><T8 Lymphocytes><Thymocyte Stimulating Factor><Tissue Growth><Trabecular Skin Carcinoma><Viral><Viral Diseases><Virus><Virus Diseases><Virus-HIV><World Health Organization><Yellow Fever><aPD-1 therapy><aPD-1 treatment><aPD1 therapy><aPD1 treatment><acute infection><adoptive cell therapy><adoptive cellular therapy><anti-PD-1 therapy><anti-PD-1 treatment><anti-PD1 therapy><anti-PD1 treatment><anti-programmed cell death 1 therapy><anti-programmed cell death protein 1 therapy><biological signal transduction><cell type><check point blockade><checkpoint blockade><chronic infection><clinical development><corona virus><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cytokine><design><designing><developmental><drug treatment><exhaust><exhaustion><high dimensionality><host response><immune check point blockade><immune checkpoint blockade><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenic><immunopathology><immunoresponse><improved><in vivo><infected with HBV><infected with hepatitis B><infected with hepatitis B virus><infection with HBV><infection with hepatitis B virus><insight><killer T cell><malignancy><metabolism measurement><metabolomics><metabonomics><mimetics><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><ontogeny><pathogenic virus><persistent infection><preconditioning><predictive biomarkers><predictive marker><predictive molecular biomarker><progenitor-like cell><programmed cell death 1><programmed cell death protein 1><programmed cell death protein 1 therapy><programmed death 1><recruit><response><response to therapy><response to treatment><self-renew><self-renewal><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><side effect><sle2><social role><statistics><stem><stem-like cell><systemic lupus erythematosus susceptibility 2><therapeutic response><therapy response><thymus derived lymphocyte><tool><transcriptomics><treatment response><treatment responsiveness><treatment strategy><tumor><viral infection><viral pathogen><virus infection><virus pathogen><virus-induced disease>