The vast majority of current human vaccines function by eliciting protective antibody responses. Neutralizing antibodies are an important component of protective immunity against a wide range of viral infections in humans and in animal models. T cell help to B cells is a fundamental aspect of adaptive immunity to viruses and the generation of immunological memory. Follicular helper CD4 T cells (Tfh) are the specialized providers of help to B cells. Tfh cells depend on expression of the transcription factor Bcl6. Tfh cells are important for the formation of germinal centers. Once germinal centers are formed, Tfh cells are needed to maintain them and to regulate germinal center B cell differentiation into plasma cells and memory B cells. There is compelling evidence that Tfh cells are limiting for the magnitude of germinal centers and hence limiting for the germinal center derived high affinity antibodies, memory B cells, and long-lived plasma cells that are the basis of long term humoral immunity. Therefore, there is substantial potential for an understanding of Tfh cells to facilitate better antiviral immune responses and vaccine-elicited humoral immunity. Despite these recent advances, our understanding of Tfh cells is still in the early stages, and the transcription factor (TF) pathways that control Tfh differentiation and define Tfli functions remain poorly understood. In Project 1, we will identify, characterize, stratify, and interconnect TFs that control Tfh differentiation and function to an acute viral infection, while also determining important TF regulators of Th1 differentiation.

Public Health Relevance

Vaccines are one of the most cost effective medical treatments in modern civilization. Antibody responses are critical components of protective immune responses to many viruses, and almost all currently licensed vaccines work on the basis of protective antibodies. The vast majority of neutralizing antibody responses to pathogens are CD4 T cell help dependent. Follicular helper (Tfh) cells are the CD4 T cells uniquely specialized for B cell help. Our lab specializes in the study of Tfh cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109976-01
Application #
8711622
Study Section
Special Emphasis Panel (ZAI1-ZL-I (J1))
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$370,131
Indirect Cost
$59,714
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Shaw, Laura A; Bélanger, Simon; Omilusik, Kyla D et al. (2016) Id2 reinforces TH1 differentiation and inhibits E2A to repress TFH differentiation. Nat Immunol 17:834-43
Martinez, Gustavo J; Hu, Joyce K; Pereira, Renata M et al. (2016) Cutting Edge: NFAT Transcription Factors Promote the Generation of Follicular Helper T Cells in Response to Acute Viral Infection. J Immunol 196:2015-9
Pedros, Christophe; Zhang, Yaoyang; Hu, Joyce K et al. (2016) A TRAF-like motif of the inducible costimulator ICOS controls development of germinal center TFH cells via the kinase TBK1. Nat Immunol 17:825-33
Crotty, Shane (2015) A brief history of T cell help to B cells. Nat Rev Immunol 15:185-9
Nance, J Philip; Bélanger, Simon; Johnston, Robert J et al. (2015) Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and utilizes the corepressor MTA3. Proc Natl Acad Sci U S A 112:13324-9
Martinez, Gustavo J; Pereira, Renata M; Äijö, Tarmo et al. (2015) The transcription factor NFAT promotes exhaustion of activated CD8⁺ T cells. Immunity 42:265-78
Hatzi, Katerina; Nance, J Philip; Kroenke, Mark A et al. (2015) BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms. J Exp Med 212:539-53
Choi, Youn Soo; Gullicksrud, Jodi A; Xing, Shaojun et al. (2015) LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nat Immunol 16:980-90
Nance, J Philip; Bélanger, Simon; Johnston, Robert J et al. (2015) Cutting edge: T follicular helper cell differentiation is defective in the absence of Bcl6 BTB repressor domain function. J Immunol 194:5599-603
Crotty, Shane; Pipkin, Matthew E (2015) In vivo RNAi screens: concepts and applications. Trends Immunol 36:315-22

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