A critical arm of the adaptive immune response is the production of highly specific, high affinity antibody (Ab). A unique subset of T cells, follicular helper T (TFH) cells act in the germinal center (GC) reaction to help B cells make high affinity Abs to antigen (Ag). GCs and high affinity Abs cannot develop in the absence of TFH cells, but at the same time, excessive development of TFH cells can lead to autoimmunity. TFH cells express the chemokine receptor CXCR5 and require the transcriptional repressor BCL6 for their development. Recently, a subpopulation of repressor T cells has been discovered, termed follicular regulatory T (TFR) cells that are critical for controlling TFH cell and GC B cells level and thus Ab responses. TFR cells express both FoxP3 and BCL6, and have properties of both regulatory T (TREG) cells and TFH cells. The current paradigm is that TFR cells appear to control the magnitude and specificity of the Ab response by limiting the production of germinal center B cells and TFH cells, however, very little is known about the regulation and functional importance of TFR cells. Most experiments used to study TFR cells had global effects on the TREG lineage and thus caveats about TFR cell functions exist. Since BCL6 also controls the development of TFR cells, the conditional deletion of BCL6 using FoxP3-cre allows a selective block in TFR cell activity. We have generated a novel mouse strain with a floxed allele of BCL6 that offers an opportunity to analyze the function of TFR cells in a novel and stable mouse system. Data from these mice show that TFR cells limit the size of the GC, and inhibit the IgG response, but do not markedly affect Ab affinity. Furthermore, we have found that unlike TFH cells, which can utilize Stat3 or Stat4 for development, TFR cells primarily rely on Stat3. These findings indicate that different cytokine environments can influence TFR cell development and thus affect the outcome of the GC. Here, we propose to study TFR cell function in terms of the Ab response and memory B cell generation, as well as the roles of different cytokines and Stat factors in controlling TFR responses. Our overall hypothesis is that the primary role of TFR cells is to limit the GC and the Ab response, and that this function is dependent upon the cytokine environment.

Public Health Relevance

Follicular regulatory T (TFR) cells are a recently discovered type of CD4 T cell whose role is specifically to negatively regulate the ability B cells to produce antibody, but how these cells function and are regulated themselves is poorly understood. These studies may lead to new therapies for the treatment of infectious disease and autoimmune disease.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI113523-01
Application #
8770786
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Ferguson, Stacy E
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Indianapolis
State
IN
Country
United States
Zip Code
46202