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Principal Investigator: Gabriel D Victora
Organization: ROCKEFELLER UNIVERSITY
Fiscal Year: 2024
Award: $797,082
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Generation of high affinity antibodies in germinal centers (GCs) is a critical step in a wide variety of clinically
relevant processes, from protection against pathogens by prior infection or vaccination to the development of
allergies and autoimmune diseases. Antibody affinity maturation follows a prototypical Darwinian framework, in
which GC B cells introduce random mutations into the antigen-binding portions of their immunoglobulin (Ig)
genes, generating variations in affinity within their progeny. Rare B cells that acquire affinity-increasing mutation
are then selectively expanded within the GC population, thus increasing the average affinity of GC B cells as a
whole, in a process we refer to as positive selection.
Despite decades of work, the precise cellular mechanisms of positive selection—in other words, how GCs “pick
out” B cells with the highest affinity—remains a topic of debate. More than 10 years ago, we provided the first in
vivo evidence in mice for a role for T follicular helper (Tfh) cells as arbiters of this selective process. In our model,
Tfh cells would sense how much peptide a B cell could present on its surface (which in turn depended on the B
cell’s affinity), providing help selectively to the highest-affinity B cells. However, despite accumulating functional
evidence for this model, selective delivery of T cell help to B cells based on their affinity has never been directly
demonstrated in physiological settings. To achieve this, we developed LIPSTIC, a method that allows us to
directly record T cell help to B cells with great precision in vivo. In Aim 1 of this project, we propose to use
LIPSTIC as a means to directly test the T cell help model in classic hapten-carrier induced GC selection models.
In Aim 2, we will follow up on this by testing our findings from mouse LIPSTIC in human vaccine-induced GCs.
In Aim 3, we use the original LIPSTIC in conjunction with two novel versions on this strategy to investigate the
dynamics of multi-antigen driven selection in influenza-induced GCs.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Active Follow-up><Address><Affinity><Allergy><Antibodies><Antibody Affinity><Antibody-Producing Cells><Antigenic Determinants><Antigenic Specificity><Antigens><Assay><Autoimmune Diseases><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Bioassay><Biological Assay><Biology><Biotin><Bp50><CD154><CD40><CD40L><CD40LG><CDW40><COVID-19 virus><COVID19 virus><Cell Body><Cell Communication><Cell Interaction><Cell model><Cell-to-Cell Interaction><Cells><Cellular model><Clonal Expansion><Cloning><CoV-2><CoV2><Development><Disease><Disorder><Engineering><Epitopes><Equilibrium><Expression Signature><FNA><Fine Needle Aspirate><Fine needle aspiration biopsy><Fine-Needle Aspiration><Gene Expression Profile><Generations><Genetic Alteration><Genetic Change><Genetic defect><Germinal Center><Grippe><HIV><Haptens><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hemagglutinin><Human><Human Immunodeficiency Viruses><Hypersensitivity><Ig Genes><Immune Globulins><Immunoglobulin Genes><Immunoglobulin-Producing Cells><Immunoglobulins><Inducer Cells><Inducer T-Lymphocytes><Infection><Infection Control><Influenza><Injections><Investigation><LAV-HTLV-III><Label><Link><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic nodes><MGC9013><Measures><Memory B Cell><Memory B-Lymphocyte><Methods><Mice><Mice Mammals><Modality><Modeling><Modern Man><Murine><Mus><Mutation><Outcome><Output><Peptides><Physiologic><Physiological><Population><Process><Proteins><RNA immunization><RNA vaccination><Reagent><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><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-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Specificity><Structure of germinal center of lymph node><Surface><System><T-Cells><T-Lymphocyte><TNFRSF5><TNFRSF5 gene><TNFSF5><TNFSF5 gene><TRAP Gene><Testing><Tumor Necrosis Factor Receptor Superfamily Member 5 Gene><Vaccination><Vaccine Design><Vaccines><Variant><Variation><Viral Antigens><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virion><Virus><Virus Diseases><Virus Particle><Virus-HIV><Vitamin H><Work><Wuhan coronavirus><active followup><antigen antibody affinity><antigen binding><antigen bound><autoimmune condition><autoimmune disorder><autoimmunity disease><balance><balance function><clinical relevance><clinically relevant><coenzyme R><combat><coronavirus disease 2019 virus><coronavirus disease-19 virus><developmental><experiment><experimental research><experimental study><experiments><follow up><follow-up><followed up><followup><gain of function><gene expression pattern><gene expression signature><genome mutation><hCoV19><immunogen><in vivo><lymph gland><lymph nodes><lymphnodes><mRNA immunization><mRNA vaccination><nCoV2><novel><p50><pathogen><peptide A><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><theories><thymus derived lymphocyte><transcriptional profile><transcriptional signature><transcriptomics><viral infection><virus antigen><virus infection><virus protein><virus-induced disease>