Document text
Principal Investigator: Hui Hu
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2024
Award: $507,907
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
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, in
particular, the initial CXCR5– versus CXCR5+ CD4+ T cell differentiation, the developmental progression
of CXCR5+CD4+ T cells to become GC-Tfh cells, and the generation of follicular helper-like memory
CD4+ T cells expressing CXCR5, are still not fully understood. Our proposal aims to fill in these
knowledge gaps with long-term goals to identify novel genes/pathways underlying the CD4+ T cell
differentiation.
In our preliminary studies, we have discovered a novel network engaging various
factors/pathways that fine-tunes CXCR5+ versus CXCR5– CD4+ T cell differentiation and regulates the
generation of cytotoxic CD4+ T cells in the early stage of CD4+ T cell response. By combining RNA-seq,
ATAC-seq, and single cell RNA-seq, our preliminary data also suggest that the PD-1+CXCR5+ pre-Tfh
cells undergo substantial further differentiation to become PD-1hiCXCR5hi GC-Tfh cells. Additionally, we
have generated novel “fate-mapping” reporter mice that will allow us to track the varied CXCR5– and
CXCR5+ memory CD4+ T cells. Thus, in this application, we aim to dissect the molecular underpinning
of the early stage CXCR5+ versus CXCR5– CD4+ T cell differentiation as well as to elucidate the
mechanisms underlying the pre- to GC-Tfh differentiation and the generation of diversified CD4+ T cell
memory.
Our work will have a profound impact on the field of CD4+ T cell differentiation. The research will
not only shed new light on our understanding of the mechanisms underlying the multiple steps of Tfh
cell differentiation but also establish new model systems for memory CD4+ T cell studies. This proposal
has the potential to provide important knowledge on how to control both the humoral and the cellular
arms of the CD4+ T cell response to aid vaccine development for new pandemic threats and help the
treatment of infectious diseases and autoimmune disorders.
Terms: <Autoimmune Diseases><B blood cells><B cell><B cell differentiation factor><B cell stimulating factor 2><B cells><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><B-Cells><B-Lymphocytes><B-cell><BACH2><BACH2 gene><BCDF><BLR1><BLR1 gene><BSF-2><BSF2><BTB and CNC Homology 2><Basal Transcription Factor><Basal transcription factor genes><Basic Leucine Zipper Transcription Factor 2><Biologic Models><Biological Models><CD25><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CXCR-5><CXCR5><Cell Body><Cell Differentiation><Cell Differentiation process><Cells><Chromatin><Communicable Diseases><Complex><Data><Development><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><Germinal Center><Goals><HPGF><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hepatocyte-Stimulating Factor><Humoral Immunities><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL2R><IL2RA><IL2RA gene><IL6 Protein><Immune response><Immunization><Immunological response><Inducer Cells><Inducer T-Lymphocytes><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Interleukin-6><Knowledge><MDR15><MGI-2><Maintenance><Maps><Memory><Mice><Mice Mammals><Model System><Modeling><Molecular><Murine><Mus><Myeloid Differentiation-Inducing Protein><PD 1><PD-1><PD1><Pathway interactions><Plasmacytoma Growth Factor><Population><Position><Positioning Attribute><Process><Proteins><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Regulation><Reporter><Research><Role><Structure of germinal center of lymph node><T cell differentiation><T cell response><T memory cell><T-Cell Subsets><T-Lymphocyte Subsets><T4 Cells><T4 Lymphocytes><TCGFR><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Vaccines><Work><antibody-based immunity><arm><autoimmune condition><autoimmune disorder><autoimmunity disease><cellular differentiation><cytokine><cytotoxic><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><emergent pandemic><emerging pandemic><global gene expression><global transcription profile><host response><immune system response><immunoresponse><infectious disease treatment><interferon beta 2><intraperitoneal><memory CD4 T cell><memory CD4 T lymphocyte><memory T lymphocyte><mouse model><murine model><new marker><new pandemic><novel><novel biomarker><novel marker><novel pandemic><pandemic concern><pandemic containment><pandemic control><pandemic mitigation><pandemic potential><pandemic response><pandemic risk><pandemic threat><pathway><programmed cell death 1><programmed cell death protein 1><programmed death 1><public health relevance><receptor><response><scATAC sequencing><scATAC-seq><scRNA-seq><single cell ATAC-seq><single cell ATAC-sequencing><single cell Assay for Transposase Accessible Chromatin sequencing><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell sequencing assay for transposase accessible chromatin><single cell transcriptomic profiling><single-cell Assay for Transposase-Accessible Chromatin with sequencing><single-cell RNA sequencing><single-cell assay for transposase-accessible chromatin using sequencing><single-cell assay for transposase-accessible chromatin-seq><sle2><social role><systemic lupus erythematosus susceptibility 2><transcription factor><transcriptome><transcriptome sequencing><transcriptomic sequencing><vaccine development><vaccine strategy>