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.
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.
|Yu, Bingfei; Zhang, Kai; Milner, J Justin et al. (2017) Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation. Nat Immunol 18:573-582|
|Milner, J Justin; Toma, Clara; Yu, Bingfei et al. (2017) Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours. Nature 552:253-257|
|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|
|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|
|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|
|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|
|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 42:265-278|
|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|
|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|
Showing the most recent 10 out of 14 publications