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Principal Investigator: Andrew Yates
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $487,050
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Immunological memory is a defining characteristic of vertebrate immune systems, and is encoded in part by populations of T lymphocytes that respond rapidly and potently to repeat exposures to pathogens. These populations are remarkably diverse in their phenotypes and trafficking patterns, and collectively form an ecosystem that reflects a lifetime's exposure to pathogens and to our environment. Yet a fundamental and pressing problem remains - we have a very limited quantitative grasp of how immunological memory is established and maintained, how new memories to infections are integrated with existing memories, and how and why these wane over time. A detailed understanding of these phenomena would guide the design of vaccines that induce durable immunity, and the development of therapies to revive and sustain T cell responses in the settings of chronic infections and cancer.
The memory encoded by circulating T cells is highly dynamic. It is sculpted by self-renewal, differentiation, loss, and supplementation or competition with newly-recruited cells. Further, in both mice and humans, memory induced by pathogens co-exists with abundant 'natural' memory T cells, which are specific for commensal and environmental antigens but provide cross-protection to new infections; and with regulatory T cells, that limit inappropriate responses. We have very little understanding of how these three populations relate.
In this project we will integrate together a powerful set of modeling and experimental approaches to confront these uncertainties. Specifically, we will develop a structured population modeling (PDE) approach to use with a fate-mapping system that tracks T cell populations throughout their life-histories. We will then combine the fate mapping system with a DNA labeling method and ODE models to define memory T cell dynamics in detail. Together, these approaches will map the development, structure, and rules of replacement of circulating memory T cell subsets in mice. We will also use data from a novel division-reporter mouse strain to model the emergence and long-term dynamics ofT cell memory to influenza infection. Finally, we will combine modeling with fate-mapping and division-reporter mice to understand how regulatory T cells are maintained, and how they impact both natural and influenza-specific memory populations.
Terms: <Activities of Daily Living><Activities of everyday life><Age><Antigens><Assay><Autoregulation><Bioassay><Biological Assay><Birth><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><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><Cancers><Cell Body><Cell division><Cells><Characteristics><Clone Cells><Complex><DNA><Data><Deoxyribonucleic Acid><Development><Ecologic Systems><Ecological Systems><Ecosystem><Environment><Event><Exposure to><Generations><Grippe><Grips><History><Homeostasis><Human><Immune memory><Immune response><Immune system><Immunity><Immunologic Memory><Immunological Memory><Immunological response><Infection><Influenza><Influenza Virus><Kinetics><Knowledge><LYT3><Label><Life><Link><Lymphocyte Subpopulations><Lymphocyte Subset><Malignant Neoplasms><Malignant Tumor><Maps><Math Models><Mediating><Memory><Methods><Mice><Mice Mammals><Modeling><Modern Man><Mouse Strains><Murine><Mus><Parturition><Pathway interactions><Pattern><Phenotype><Physiological Homeostasis><Population><Population Heterogeneity><Proliferating><Recording of previous events><Regulatory T-Lymphocyte><Reporter><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><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><Structure><Supplementation><Survival Analyses><Survival Analysis><System><T cell regulation><T cell response><T memory cell><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T8 Cells><T8 Lymphocytes><Time><Treg><Uncertainty><Vaccine Design><Vaccines><ages><anamnestic reaction><chronic infection><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><cross immunity><cross protection><cross reactivity><daily living function><daily living functionality><develop therapy><developmental><diverse populations><doubt><experiment><experimental research><experimental study><experiments><flu infection><flu virus infection><functional ability><functional capacity><grasp><heterogeneous population><histories><host response><immune system response><immunogen><immunopathology><immunoresponse><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><influenzavirus><intervention development><life history><malignancy><mathematic model><mathematical model><mathematical modeling><memory CD4 T cell><memory CD4 T lymphocyte><memory T lymphocyte><memory encoding><neoplasm/cancer><novel><pathogen><pathway><persistent infection><population diversity><recruit><regulatory T-cells><response><secondary immune response><self-renew><self-renewal><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><success><therapy development><thymus derived lymphocyte><tool><trafficking><treatment development><tumor>