Regulation of Tfh cell differentiation and humoral immunity
Document text
Principal Investigator: Hui Hu Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM Fiscal Year: 2021 Award: $491,617 Funding agency: National Institute of Allergy and Infectious Diseases Project Summary CD4+ T follicular helper (Tfh) cells are essential for germinal center (GC) responses and long- term humoral immunity. However, the complex regulation that determines the differentiation of Tfh cells, their developmental progression in GC, and their number and function in helping GC B cell differentiation and antibody affinity selection, are still not fully understood. Our long-term goals are to identify novel pathways underlying the differentiation of Tfh cells and design new strategies to manipulate humoral responses for treatment of infectious diseases and autoimmune disorders and to aid vaccine development. Recently we have identified transcription factor Foxp1 as a rate-limiting and critical negative regulator of Tfh cell differentiation, which drastically affects both the kinetics and the magnitude of the antibody responses. Our new preliminary data now start to reveal that Foxp1 engages a complex network of regulators that are coordinated to suppress Tfh cell differentiation as well as Tfh help to B cells at different stages/steps of the GC response. In this application, we aim to identify Foxp1 targets and elucidate the molecular mechanisms by which Foxp1 regulates Tfh cell differentiation. In addition, we will further delineate how Foxp1-mediated regulation of Tfh cell differentiation affects GC B cell development, antibody affinity selection and chronic infection. Our study will not only reveal new components of the transcriptional regulation in Tfh cell differentiation, but also provide fundamental mechanistic insights in the regulation of GC B cell responses and antibody affinity selection. Terms: <Affect><Antibody Affinity><Antibody Response><Attenuated><Autoimmune Diseases><Autoimmune Status><Autoimmunity><B blood cells><B cell><B cell differentiation><B cells><B lymphocyte differentiation><B-Cell Development><B-Cells><B-Lymphocytes><B-cell><BACH2><BACH2 gene><BLR1><BLR1 gene><BTB and CNC Homology 2><Basal Transcription Factor><Basal transcription factor genes><Basic Leucine Zipper Transcription Factor 2><CD152><CD152 Antigen><CD152 Gene><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><CXCR-5><CXCR5><Candidate Disease Gene><Candidate Gene><Cell Body><Cell Communication and Signaling><Cell Count><Cell Death><Cell Differentiation><Cell Differentiation process><Cell Number><Cell Signaling><Cells><Chronic><Clinical><Communicable Diseases><Complex><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Data><Development><FOXP1><FOXP1 gene><Forkhead Box P1><General Transcription Factor Gene><General Transcription Factors><Germinal Center><Glutamine-Rich Factor 1><Goals><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Humoral Immunities><ITIM><Immune response><Immunological response><Immunoreceptor Tyrosine-Based Inhibitory Motif><Inducer Cells><Inducer T-Lymphocytes><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Intracellular Communication and Signaling><Kinetics><Lead><MDR15><Mediating><Messenger RNA><Molecular><PD 1><PD-1><PD1><Pathway interactions><Pb element><Play><Proliferating><QRF1><Receptor Protein><Receptor Up-Regulation><Regulation><Role><Signal Transduction><Signal Transduction Systems><Signaling><Structure of germinal center of lymph node><T-Cell Activation><T-Cells><T-Lymphocyte><T-Stage><T4 Cells><T4 Lymphocytes><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Tumor stage><Viral Diseases><Virus Diseases><antibody-based immunity><antigen antibody affinity><autoimmune condition><autoimmune disorder><biological signal transduction><chronic infection><cytotoxic T-lymphocyte antigen 4><design><designing><develop a vaccine><development of a vaccine><developmental><functional genomics><heavy metal Pb><heavy metal lead><host response><immune system response><immunoresponse><infectious disease model><infectious disease treatment><insight><mRNA><necrocytosis><new marker><novel><novel biomarker><novel marker><overexpress><overexpression><pathway><persistent infection><programmed cell death 1><programmed cell death protein 1><programmed death 1><public health relevance><receptor><response><response to treatment><sle2><social role><systemic lupus erythematosus susceptibility 2><therapeutic response><thymus derived lymphocyte><transcription factor><treatment response><vaccination study><vaccination trial><vaccine development><vaccine formulation><vaccine study><vaccine trial><viral infection><virus infection><virus-induced disease>