Document text
Principal Investigator: Gabriel D Victora
Organization: ROCKEFELLER UNIVERSITY
Fiscal Year: 2019
Award: $454,516
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Germinal centers (GCs) are site of antibody somatic hypermutation (SHM) and affinity maturation, and are
therefore essential for effective humoral immune responses to pathogens. Efficient affinity maturation in GCs
requires that B cells cycle between two different cell states, associated with distinct microanacomical
compartments: (i) a “proliferation” mode, when B cells divide and undergo SHM, which takes place in the dark
zone (DZ) of the GC; and (ii) a “selection” mode, when mutated B cells compete with each other based on their
affinity for antigen, which takes place in the GC light zone (LZ). While our previous work defined the
transcriptional programs broadly associated with LZ and DZ states, our understanding of how cells decide
when to transition between one state and another remains incomplete. For example, we do not understand the
signals that trigger DZ B cells to stop proliferating and return to the LZ, nor do we know whether LZ and DZ
cells can be further parsed into additional transcriptionally distinct states that associated with different stages of
GC selection. Here, we propose to combine in vivo models of synchronized GC selection with novel mouse
genetic models, treatment with signaling inhibitors, and single-cell mRNA sequencing to determine the full
complement of GC transcriptional states and to address how these states are associated with GC selection. A
clear definition of these programs will improve our understanding of how GC B cell selection and affinity
maturation are controlled, with implications for vaccine design. Moreover, determining how GC B cell
proliferation is controlled will further our understanding of GC-derived B cell lymphomas, which rely on similar
mechanisms as GCs to achieve sustained proliferation.
Terms: <ATGN><Active Follow-up><Address><Affinity><Alleles><Allelomorphs><Anatomic><Anatomic Sites><Anatomic Structure, System, or Substance><Anatomic Structures and Systems><Anatomic structures><Anatomical Sciences><Anatomy><Anatomy Qualifier><Antibodies><Antibody Affinity><Antigens><Autoimmune Diseases><B Cell Proliferation><B blood cells><B cell><B cells><B lymphoma><B-Cell Lymphomas><B-Cells><B-Lymphocytes><B-cell><CCND2><CCND2 gene><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Cycle><Cell Division Cycle><Cell Growth in Number><Cell Interaction><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell-to-Cell Interaction><Cells><Cellular Proliferation><Communicable Diseases><Complement><Complement Proteins><Dark Cell><Dissection><Equilibrium><Event><Follicular Dendritic Cells><Gene Transcription><Generations><Genetic><Genetic Models><Genetic Transcription><Germinal Center><Germinoblastic Sarcoma><Germinoblastoma><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Heterogeneity><Ig Genes><Ig Somatic Hypermutation><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune Globulins><Immune response><Immunoglobulin Genes><Immunoglobulin Somatic Hypermutation><Immunoglobulins><Immunological response><Individual><Inducer Cells><Inducer T-Lymphocytes><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Intercalated Cell><Intracellular Communication and Signaling><KIAK0002><Laboratories><Lead><Light><Lupus><Lymphoma><Maintenance><Malignant Lymphoma><Mice><Mice Mammals><Modeling><Molecular><Murine><Mus><Mutate><Output><Pathway interactions><Pb element><Photoradiation><Plasmablast><Process><Proliferating><Public Health><Publications><RNA Expression><Reaction><Receptor Protein><Research><Reticulolymphosarcoma><Role><S Period><S Phase><SCmRNAseq><Scientific Publication><Series><Signal Transduction><Signal Transduction Systems><Signaling><Site><Structure><Structure of germinal center of lymph node><Synthesis Period><Synthesis Phase><T-Cells><T-Lymphocyte><Testing><Transcription><Vaccination><Vaccine Design><Work><active followup><antigen antibody affinity><autoimmune disorder><balance><balance function><base><biological signal transduction><cyclin D2><cyclin D3><experiment><experimental research><experimental study><fighting><follow up><follow-up><followed up><followup><gain of function mutation><global gene expression><global transcription profile><heavy metal Pb><heavy metal lead><host response><immunogen><immunoresponse><improved><in vivo><in vivo Model><inhibitor><inhibitor/antagonist><mutant><novel><pathogen><pathway><photoactivation><programs><receptor><response><scRNA-seq><single cell RNA-seq><single cell analysis><single cell mRNA sequencing><single-cell RNA sequencing><social role><somatic hypermutation><thymus derived lymphocyte><transcriptome>