Control of autoimmunity by follicular helper T cells and BCL6

Project: Research project

Description

DESCRIPTION (provided by applicant): CD4 T helper cells are critical for the proper orchestration of the immune response and are essential for helping B cells make high affinity antigen-specific antibody. Follicular helper T (Tfh) cells are a recently characterized subset of CD4 T cells whose role is specifically to help B cells produce antibody, in part by promoting the germinal center reaction. However, deregulated development of Tfh cells can lead to autoimmune disease. Tfh cells are localized to B cell follicles and thus express the chemokine receptor CXCR5. Tfh cells are also characterized by high expression of the transcription repressor BCL6, and secretion of the B cell stimulatory cytokine IL-21. Recent data indicates that BCL6 is the master transcriptional regulator for Tfh cells: forced BCL6 expression can induce the Tfh phenotype in T cells, and Tfh cells cannot develop in the absence of BCL6. In this proposal, we seek to take advantage of the central role for BCL6 in Tfh development and function to better understand the link between Tfh cells and auto-immunity. Our hypothesis is that increased Tfh activity promoted by BCL6 can lead to non-specific antibody responses and eventually to autoimmunity, while blockade of BCL6 activity can block Tfh function and thus inhibit autoimmune disease progression. This hypothesis will be tested in the specific aims described below. This study will provide information that is critical for the manipulation of Tfh cells in vaccine development. Further, these experiments may lead to novel treatments for autoimmune diseases such as lupus. PUBLIC HEALTH RELEVANCE: CD4 T helper cells are critical for the proper orchestration of the immune response, and CD4 T cells are particularly important in helping B cells in make antigen-specific antibody that fights disease. Follicular helper T (Tfh) cells are a recently discovered type of CD4 T cells whose role is specifically to help B cells produce antibody. However, Tfh cells can also promote autoimmune disease. Here we want to probe the relationship between Tfh cells and autoimmunity using a novel system, and also use a novel drug to block Tfh function. These studies may lead to new therapies for the treatment of autoimmune disease.
StatusFinished
Effective start/end date5/15/104/30/12

Funding

  • National Institutes of Health: $192,500.00
  • National Institutes of Health: $228,690.00

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Helper-Inducer T-Lymphocytes
Autoimmunity
B-Lymphocytes
Autoimmune Diseases
Antibodies
T-Lymphocytes
Antigens
Germinal Center
Chemokine Receptors
T-Lymphocyte Subsets
Antibody Formation
Disease Progression
Immunity
Vaccines
Public Health
Cytokines
Phenotype
Pharmaceutical Preparations

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)