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.

Public Health Relevance

In humoral immune responses, T follicular helper (Tfh) cells regulate the kinetics, magnitude and quality of antibody responses. Our study to identify novel pathways underlying the differentiation of Tfh cells will provide fundamental information for designing new strategies to manipulate humoral responses in a wide range of clinical settings including infectious diseases, autoimmunity and vaccine development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI130232-01A1
Application #
9392680
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
2017-06-05
Project End
2022-05-31
Budget Start
2017-06-05
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
$573,134
Indirect Cost
$172,687
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294