CD4 T helper cells are critical for the proper function 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. In the absence of Tfh cells, germinal centers and secondary antibody responses fail to develop. Excessive development of Tfh cells can lead to autoimmunity. Tfh cells are localized to B cell follicles due to their expression of 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 studies have shown that BCL6 is the master transcriptional regulator for Tfh cells: forced BCL6 expression can induce a Tfh phenotype in T cells, and Tfh cells cannot develop in the absence of BCL6. However, what is lacking for the study of Tfh cells is a convenient in vivo system for analyzing the function of Tfh cells. While BCL6 knockout mice lack Tfh cells, they also have a large number of other defects and are difficult to breed. We are currently developing mice in which BCL6 is specifically mutated in CD4 T cells. We propose that this mouse model will be highly useful and vastly improved model for the study of Tfh cell function. Furthermore, this mouse will provide essential and final confirmation that Tfh cells are intrinsically dependent upon BCL6 for their development. INNOVATION: This study uses a completely novel mouse model to analyze Tfh cell function. Additionally, we propose to develop an innovative transgenic mouse that can be used to track the Tfh cell fate. Overall, these experiments will give insights into the development of Tfh cells and will lead to the development of a critical new tool for studying Tfh cell function. IMPACT: These experiments will provide information that is critical for understanding the development of the antibody response to fight infectious disease. These studies should also accelerate the development of vaccines that target Tfh cells, as well as impact studies on autoantibody production.

Public Health Relevance

CD4 T helper cells are critical for the proper 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 subset of CD4 T cells whose role is specifically to help B cells produce antibody. Here we propose to develop and characterize novel biological systems to study Tfh cell differentiation and function.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Ferguson, Stacy E
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Mathew, Rebecca; Mao, Ai-ping; Chiang, Andrew H et al. (2014) A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation. J Exp Med 211:1137-51
Pham, Duy; Walline, Crystal C; Hollister, Kristin et al. (2013) The transcription factor Twist1 limits T helper 17 and T follicular helper cell development by repressing the gene encoding the interleukin-6 receptor * chain. J Biol Chem 288:27423-33
Hollister, Kristin; Kusam, Saritha; Wu, Hao et al. (2013) Insights into the role of Bcl6 in follicular Th cells using a new conditional mutant mouse model. J Immunol 191:3705-11