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. A major goal o vaccination against viruses, bacteria, or parasites is to optimize long-term high-affinity antibody responses, but the best strategy for achieving this result is not clear. We have found that the intracellular adaptor SAP and the SLAM family receptors are critical for germinal centers (GC) and long term antibody responses to virtually all pathogens because of their importance in Tfh cell and T:B interactions. These signals are conserved in humans, and mutations in Sh2d1a, the gene encoding SAP, are the cause of a severe human immunodeficiency that, when left untreated, frequently results in death associated with a variety of infections. In the initial fundng period of this R01 Tfh cells were generally unrecognized. We helped establish that Tfh cell are a distinct type of differentiated CD4 T cell, that required Bcl6 for their differentiation, that are required for GCs and most B cell memory, and that depend on signals from both DCs and B cells as APCs. We recently made the surprising finding that SAP is essential to block powerful negative signaling by the SLAM family receptor LY108. However, the mechanism remains to be shown. We now propose to determine the mechanism. Furthermore, positive signaling in Tfh function is likely mediated by several of the SLAM family members, including LY108. Therefore, we will determine which SLAM family receptors provide positive signals. Finally, much of our efforts were to establish that Tfh differentiation is a multistage, multifactorial process. SAP is required for full Tfh differentiation, but is not required for early Tfh differentiation, and thereore we continue to intensively investigate early signals required for Tfh differentiation in vivo and i vitro.

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. This R01 is focused on understanding Tfh differentiation and function, particularly examining the roles of SAP and SLAM family members, which are known to be essential in both mice and man for protective immunity.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01AI072543-06
Application #
8785629
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ferguson, Stacy E
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
Locci, Michela; Wu, Jennifer E; Arumemi, Fortuna et al. (2016) Activin A programs the differentiation of human TFH cells. Nat Immunol 17:976-84
Crotty, Shane (2015) A brief history of T cell help to B cells. Nat Rev Immunol 15:185-9
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
Chen, Runqiang; Bélanger, Simon; Frederick, Megan A et al. (2014) In vivo RNA interference screens identify regulators of antiviral CD4(+) and CD8(+) T cell differentiation. Immunity 41:325-38
Xiao, Nengming; Eto, Danelle; Elly, Chris et al. (2014) The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells. Nat Immunol 15:657-66

Showing the most recent 10 out of 28 publications