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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Rothermel, Annette L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
Zip Code
Sawant, Deepali V; Wu, Hao; Yao, Weiguo et al. (2015) The transcriptional repressor Bcl6 controls the stability of regulatory T cells by intrinsic and extrinsic pathways. Immunology 145:11-23
LaPensee, Christopher R; Lin, Grace; Dent, Alexander L et al. (2014) Deficiency of the transcriptional repressor B cell lymphoma 6 (Bcl6) is accompanied by dysregulated lipid metabolism. PLoS One 9:e97090
Hollister, Kristin; Chen, Yuxin; Wang, Shixia et al. (2014) The role of follicular helper T cells and the germinal center in HIV-1 gp120 DNA prime and gp120 protein boost vaccination. Hum Vaccin Immunother 10:1985-92
Sawant, Deepali V; Wu, Hao; Kaplan, Mark H et al. (2013) The Bcl6 target gene microRNA-21 promotes Th2 differentiation by a T cell intrinsic pathway. Mol Immunol 54:435-42
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
Sawant, Deepali V; Sehra, Sarita; Nguyen, Evelyn T et al. (2012) Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing Gata3 function. J Immunol 189:4759-69