Transcriptional and metabolic regulation of vaccine-elicited CD8+ T cell responses

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Principal Investigator: Ross M Kedl
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $460,469
Funding agency: National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY
Due to the overwhelming success of the new mRNA vaccines during the SARS-CoV2 pandemic, vaccines have
entered the public consciousness to a level not seen since the days of smallpox eradication and the polio
epidemic. It seems reasonable to assume that the established rules governing T cell responses to infections
might be useful in developing better subunit vaccine formulations. However, there is mounting evidence that the
immunological mechanisms relevant to adjuvant-elicited cellular immunity are vastly different than those
observed in response to infectious challenge. Over the last 20 years, we have published extensively on a growing
list of factors that highlight the mechanistic distinctions between vaccine-elicited (Tvacs) and infection-elicited
(Tinf) T cell responses in mice and non-human primates. Our most recent data has revealed additional features
mechanistically unique to Tvacs. Whereas Tinf split their functions between 2 different cell types and either divide
or become memory, Tvacs do both within the same cell. Our data support an entirely novel model of CD8+ T
cell activation whereby two transcription factors normally opposed to one another in function instead cooperate
to sustain Tvacs exponential clonal expansion as well as a memory cell fate. The goals of this project will be to
understand how these transcription factors cooperate instead of competing to support a vaccine-elicited T cell's
transcriptional and metabolic needs.

Terms: <ATAC sequencing><ATAC-seq><ATACseq><Abbreviations><Acute Poliomyelitis><Adjuvant><Assay for Transposase-Accessible Chromatin using sequencing><Basal Transcription Factor><Basal transcription factor genes><Biology><Biomass><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><Cell Body><Cell Communication and Signaling><Cell Function><Cell Mediated Immunology><Cell Physiology><Cell Process><Cell Signaling><Cell-Mediated Immunity><Cells><Cellular Function><Cellular Immunity><Cellular Physiology><Cellular Process><Cellular biology><ChIP Sequencing><ChIP-seq><ChIPseq><Clinic><Clonal Expansion><Conscious><Consciousness><Data><Development><Disease><Disorder><Epidemic><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Evaluation><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FKHR><FOXO1><FOXO1A><FOXO1A gene><FRAP1><FRAP1 gene><FRAP2><Forkhead Box O1A><Forkhead in Rhabdomyosarcoma><Frequencies><Funding><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Gluconeogenesis><Glycolysis><Goals><IL-15><IL15><IL15 Protein><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Infection><Inflammation><Interleukin-15><Interleukin-15 Precursor><Intracellular Communication and Signaling><Investigation><L monocytogenes><L. monocytogenes><LCM Viruses><LCMV><Lipids><Listeria monocytogenes><Lymphocytic choriomeningitis virus><MGC9721><Mechanistic Target of Rapamycin><Mediating><Memory><Metabolic><Methods><Mice><Mice Mammals><Mitochondria><Modeling><Murine><Mus><NGS Method><NGS system><Nature><Oxidation-Reduction><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><PPAR><Peroxisome Proliferator-Activated Receptors><Phenotype><Polio><Poliomyelitis><Population><Primates><Primates Mammals><Production><Productivity><Proliferating><Publishing><RAFT1><RNA Expression><RNA Seq><RNA sequencing><RNA vaccine><RNA-based vaccine><RNAseq><Redox><Regulation><Research><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><SIRT1><SIRT1 gene><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 Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sirtuin 1><Subcellular Process><Subunit Vaccines><T cell response><T memory cell><T-Cell Activation><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Vaccines><Yellow Fever><activate T cells><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><cell biology><cell type><chromatin immunoprecipitation-sequencing><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><develop a vaccine><develop vaccines><development of a vaccine><developmental><epigenetically><fatty acid oxidation><glucose biosynthesis><insight><mRNA vaccine><mRNA-based vaccine><mTOR><mammalian target of rapamycin><memory T lymphocyte><mitochondrial><next gen sequencing><next generation sequencing><nextgen sequencing><non-human primate><nonhuman primate><novel><oxidation reduction reaction><pathogen><programs><response><scRNA-seq><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small pox eradication><smallpox eradication><social role><success><thymus derived lymphocyte><transcription factor><transcriptome sequencing><transcriptomic sequencing><vaccine development><vaccine formulation><variants of concern>