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Principal Investigator: Jie Sun
Organization: UNIVERSITY OF VIRGINIA
Fiscal Year: 2024
Award: $569,694
Funding agency: National Institute of Allergy and Infectious Diseases
Summary/Abstract
Tissue-resident memory T cells (TRM) that park within the non-lymphoid tissue provide superior immunity
against a variety of pathogens including influenza virus infection. The mechanisms regulating CD8 TRM
maintenance, heterogeneity, protective and pathological functions are incompletely understood. Our recent
data have identified a novel protective CD8 TRM population that co-exhibits both exhausted and
conventional memory CD8 T cell features following acute influenza infection. Unlike the conventional
circulating memory CD8 T cells that are maintained in a MHC-I independent way, the survival and
maintenance of these PD-1hi TRM cells require persistent MHC-I and TCR signaling. Based on these prelim
data, we propose to further elucidate the underlying mechanisms by which these PD-1hi TRM are maintained in
the lung. We hypothesize the intrinsic CD28 and PD-1 signaling, specifically in lung-resident CD8 T cells,
balances the maintenance, protective function and fibrogenic activities of these PD-1hi TRM following influenza
virus infection (Aim 1). Furthermore, we will test the hypothesis that the expression of the transcription factor
Klf10 in CD8 T cells is vital for the maintenance and the function of these PD-1hi TRM (Aim 2). In addition, we
will determine whether it is possible to uncouple the pathogenic activities from the protective function of TRM, so
we may specifically provoke the protective function, but not the pathogenic activities of TRM for future vaccine
design and/or immunotherapies (Aim 3).
Relevance statement
Each year, influenza virus infects 5–10% of adults and 20–30% of children, killing as many as 500,000 people
globally. In addition to the acute morbidity and mortality, it is increasingly appreciated that influenza virus
infection could lead to the development of chronic lung conditions including pulmonary fibrotic responses.
Currently, little is known about the etiology of the development of chronic lung sequelae following influenza
virus infection. The successful completion of this study will provide insights for developing interventions to
promote the complete recovery of the tissue while minimizing the development of chronic lung conditions
following acute respiratory viral infections. Furthermore, understanding the cellular and molecular mechanisms
regulating the maintenance of lung protective TRM responses following influenza infection and/or immunization
may aid the design of future influenza therapeutics and influenza vaccines.
Terms: <(TNF)-α><0-11 years old><21+ years old><Ablation><Acute><Acute Disease><Adopted><Adult><Adult Human><Basal Transcription Factor><Basal transcription factor genes><Body Tissues><CD28><CD28 gene><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cachectin><Causality><Cell Body><Cell Communication and Signaling><Cell Growth and Maintenance><Cell Maintenance><Cell Signaling><Cells><Child><Child Youth><Children (0-21)><Chronic><Clinical><Clinical Research><Clinical Study><Data><Development><Equilibrium><Etiology><Exhibits><Fibrotic lesions in lung><Flu vaccination><Future><General Transcription Factor Gene><General Transcription Factors><Goals><Granzyme><Heterogeneity><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune Interferon><Immunity><Immunology><Impairment><In Situ><Infection><Inflammation><Influenza Therapeutic><Influenza Vaccines><Influenza Virus><Influenza immunization><Influenza vaccination><Injury><Interferon Gamma><Interferon Type II><Intervention><Intervention Strategies><Intracellular Communication and Signaling><LYT3><Lead><Left><Lung><Lung Respiratory System><Lung Tissue Fibrosis><Lung scar><Lung tissue scar><Macrophage-Derived TNF><Maintenance><Mediating><Memory><Molecular><Molecular Target><Monocyte-Derived TNF><Morbidity><Morbidity - disease rate><PD 1><PD-1><PD-L1 blockade><PD-L1 therapy><PD-L1 treatment><PD1><PDL1 blockade><PDL1 therapy><PDL1 treatment><Parabiosis><Pathogenicity><Pathologic><Patients><Pb element><Persons><Population><Primary Infection><Prophylactic vaccination against influenza><Pulmonary Fibrosis><Pulmonary Scar><Pulmonary Tissue fibrosis><Receptor Protein><Recovery><Rejuvenation><Resolution><Role><Scarring at the lung><Scarring in the lung><Science><Signal Transduction><Signal Transduction Systems><Signaling><T cell response><T44><T8 Cells><T8 Lymphocytes><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Tissues><Transcription Factor Proto-Oncogene><Transcription factor genes><Translating><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vaccine Design><Viral Respiratory Tract Infection><aPD-L1 therapy><aPD-L1 treatment><acute disease/disorder><acute disorder><acute infection><adulthood><anti programmed cell death ligand 1 therapy><anti programmed cell death ligand 1 treatment><anti programmed cell death protein ligand 1 therapy><anti programmed cell death protein ligand 1 treatment><anti-PD-L1 blockade><anti-PD-L1 therapy><anti-PD-L1 treatment><anti-PDL1 therapy><anti-PDL1 treatment><anti-microbial><antimicrobial><balance><balance function><biological signal transduction><causation><compare to control><comparison control><design><designing><developmental><disease causation><exhaust><fibrosis in the lung><fibrotic lung><flu immunisation><flu infection><flu therapeutic><flu vaccine><flu virus infection><flu virus vaccine><heavy metal Pb><heavy metal lead><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><influenza virus vaccination><influenza virus vaccine><influenzavirus><injuries><insight><interventional strategy><kids><lFN-Gamma><lung fibrosis><mortality><novel><pathogen><programmed cell death 1><programmed cell death protein 1><programmed death 1><pulmonary><receptor><resident memory T cell><resolutions><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><social role><systemic lupus erythematosus susceptibility 2><therapeutic vaccine><tissue resident memory T cell><transcription factor><treatment vaccines><vaccination against influenza><vaccine against flu><vaccine against influenza><vaccine for immunotherapy><vaccine for the treatment><vaccine for treatment><vaccine immunotherapy><vaccine-based immunotherapy><viral respiratory infection><youngster><αPD-L1 therapy><αPD-L1 treatment>