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Principal Investigator: Donna L. Farber
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2022
Award: $820,875
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Immune system development during infancy and childhood sets the stage for a lifetime of protective immunity.
Infants and children are known to be more susceptible to ubiquitous respiratory and mucosal pathogens for
which adults have prior exposures. However, our recent experience in the COVID-19 pandemic, in which
children were markedly less susceptible than adults to disease from infection with the novel respiratory virus
SARS-CoV-2, indicate that children's immune systems can be highly effective to newly encountered
pathogens. The diverse repertoire of naïve T cells, their ability to differentiate to tissue homing effector cells,
which mediate pathogen clearance at infection sites, and the subsequent generation of long-lived memory T
cells are critical events in immune responses that are not defined in children. Identifying the mechanisms by
which T cells respond to antigenic challenges and establish immunological memory throughout infancy and
childhood are essential for improving vaccines and immunotherapies to protect the next generation. My
laboratory has been studying early life immunity in mouse models and novel human samples, including tissues
from infant and pediatric organ donors, with a focus on how protective tissue resident memory T cells (TRM)
become established in early life and mature over childhood. We pioneered the study of human tissue immunity
in organ donor tissues, identifying that the majority of T cells across tissues in the body are TRM, which begin
to form in early life in intestines and mature over age. We have identified fundamental and intrinsic differences
in infant compared to adult T cells at the earliest stages in T cell activation and have investigated anti-viral
immunity to SARS-CoV-2 in different pediatric cohorts. Our central hypothesis is that pediatric T cell responses
are distinct due to intrinsic signaling mechanisms, the specific tissue environment, and the antigenic exposure
history. In this study, we will build on our results, human samples, and cohorts to elucidate mechanisms for the
distinct responses of pediatric T cells and their differentiation fate, maturation in tissues, and evolving response
to vaccines. In aim 1, we will identify mechanisms for the distinct activation of pediatric naïve T cells, including
how early events during T cell conjugate formation and cell division impact cell fate in early life and childhood
for mouse and human T cells. In aim 2, we will elucidate TRM differentiation pathways and the role of the
tissue in TRM maturation by high dimensional single cell profiling of human TRM in intestines and lungs across
all ages of childhood, and use mouse models to address the role of persistence and tissue environment in
TRM maturation. In aim 3, we will analyze vaccine-specific immune responses and evolution over childhood in
established cohorts of children who previously had different clinical manifestations of SARS-CoV-2 infection, or
were not infected. We will assess virus-specific T cell and antibody responses to the current COVID mRNA
vaccines over time and age. Together, the proposed studies will comprehensively define immune system
maturation over this critical and formative window of childhood.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><21+ years old><Address><Adult><Adult Human><Age><Airway mucosa><Antibodies><Antibody Response><Antigen-Presenting Cells><Antigens><Blood><Blood Reticuloendothelial System><Blood Sample><Blood specimen><Body Tissues><COVID><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 immunity><COVID-19 infection><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 vaccine><COVID-19 virus><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 immunity><COVID19 infection><COVID19 pandemic><COVID19 public health crisis><COVID19 vaccine><COVID19 virus><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell division><Cells><Child><Child Youth><Childhood><Children (0-21)><Clinical><CoV disease><CoV-2><CoV2><Collaborations><Development><Disease><Disorder><Effector Cell><Environment><Event><Evolution><Exhibits><Exposure to><Expression Signature><Gene Expression><Gene Expression Profile><Generations><Genes><Grippe><Health><History><Homing><Human><Immune><Immune mediated therapy><Immune memory><Immune response><Immune system><Immunes><Immunity><Immunologic Memory><Immunological Memory><Immunological response><Immunologically Directed Therapy><Immunotherapy><Individual><Infant><Infection><Inflammatory><Influenza><Intestinal><Intestines><Intracellular Communication and Signaling><Knowledge><Laboratories><Life><Lung><Lung Respiratory System><MHC Receptor><MIS-C><Major Histocompatibility Complex Receptor><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Molecular Fingerprinting><Molecular Profiling><Mucosa><Mucosal Tissue><Mucous Membrane><Multiorgan Inflammatory Syndrome in Children><Multisystem Inflammatory Syndrome in Children><Murine><Mus><Nature><Organ Donor><Organ Procurements><Pathway interactions><Pediatric cohort><Phenotype><Population><Process><Property><RNA vaccine><RNA-based vaccine><Recording of previous events><Respiratory Mucosa><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 immunity><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 immunity><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Site><Syndrome><Systems Development><T cell response><T memory cell><T-Cell Activation><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><Time><Tissue Donors><Tissue Sample><Tissues><Vaccination><Vaccines><Virus><Wuhan coronavirus><accessory cell><adaptive immune response><adaptive immunity><adulthood><ages><allergic/immunologic body system><allergic/immunologic organ system><anamnestic reaction><anti-viral immunity><antiviral immunity><base><biological signal transduction><bowel><child patients><cohort><corona virus disease><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus disease 2019 vaccine><coronavirus disease><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 immunity><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 vaccine><coronavirus disease-19 virus><design><designing><developmental><experience><gene expression pattern><gene expression signature><global gene expression><global transcription profile><hCoV19><high dimensionality><host response><human tissue><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunity against COVID-19><immunity against COVID19><immunity against SARS-CoV-2><immunity against Severe acute respiratory syndrome coronavirus 2><immunity against coronavirus disease 2019><immunity to COVID-19><immunity to COVID19><immunity to SARS-CoV-2><immunity to Severe acute respiratory syndrome coronavirus 2><immunity to coronavirus disease 2019><immuno therapy><immunogen><immunological synapse><immunoresponse><improved><infancy><infantile><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><insight><mRNA vaccine><mRNA-based vaccine><memory T lymphocyte><molecular profile><molecular signature><mouse model><mucosal site><multisystem inflammatory syndrome of children><murine model><nCoV2><next generation><novel><pathogen><pathogenic virus><pathway><pediatric><pediatric inflammatory multisystem syndrome><pediatric patients><prevent><preventing><pulmonary><respiratory infection virus><respiratory virus><response><secondary immune response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><thymus derived lymphocyte><transcriptional profile><transcriptional signature><transcriptome><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine for novel coronavirus><viral pathogen><virus pathogen><youngster>