Germinal centers (GCs) are of tremendous importance to human health. Not only do they generate the high-affinity antibodies that make vaccination possible and are the cause of allergies and humoral autoimmune diseases, but they are also the source of the genetic lesions that trigger most B cell malignancies. There is a fundamental gap in our understanding of how the selection of B cell clones during the GC reaction can generate the highly mutated antibodies necessary, for example, for broad neutralization of HIV. This gap represents a major obstacle to the development of effective vaccines for many human diseases. The long-term goal of the investigator's research is to develop a detailed understanding, at the cellular and molecular levels, of all aspects of the B cel response, from first contact with antigen to production of high-affinity antibodies. Recent work by the investigator and others has underscored the importance of interaction between T follicular helper (Tfh) cells and B cells in GC selection. The objective of this application is to investigate specific aspects of this interaction, especially with regard to its influence on B cell fate choice. The rationale for the proposed research is that, because Tfh cells control key aspects of the GC-such as magnitude, persistence, and selective pressure-understanding the relationship between B cells and Tfh cells should improve our ability to coax GCs into producing the highly mutated antibodies required for broad neutralization. In this context, three specific aims are proposed. First, in vivo photoactivation by multiphoton microscopy, a method developed by the investigator, will be used to determine the role of accessibility of GCs to incoming Tfh cells in determining how T cell specificity in the GC is controlled. The hypothesis in this aim is that GCs are open to the ingress and egress of Tfh cells, and that this openness impacts the clonality and specificity of GC T cells and the longevity of GC reactions. Second, a method to trigger selection of GC B cells by Tfh cells in vivo, also developed by the investigator, will be used to probe the gene expression changes that are induced in B cells upon selection. The hypothesis in this aim is that Tfh cell help triggers specific gene expression programs that determine the subsequent fate choices made by of GC B cells. Finally, the investigator proposes to develop a novel approach to measuring the history of interactions between Tfh cells and B cells in vivo. This technique will allow for interactions between immune cells to be probed and quantified in a technically much simpler manner, and in a more physiological context, than by currently available methods. The proposed research is significant because it will contribute to our understanding of key aspects of GC selection at the cellular and molecular levels, especially with regard to its reliance on T cell help. This knowledge should allow better control over the GC reaction, especially with regard to its longevity and output. Ability to control these aspects of te GC is a prerequisite for achieving broad neutralization by vaccination.

Public Health Relevance

The proposed research is relevant to public health because it addresses the question of how the antibodies that protect us from infections and cause allergies and certain autoimmune diseases are generated. Deeper understanding of these processes can lead to improved treatment and vaccination strategies. Thus, the proposed research is relevant to the NIH's mission of developing basic knowledge that will help reduce the burden of human disease.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Early Independence Award (DP5)
Project #
5DP5OD012146-04
Application #
8918325
Study Section
Special Emphasis Panel (ZRG1-BBBP-E (53))
Program Officer
Basavappa, Ravi
Project Start
2012-09-25
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
4
Fiscal Year
2015
Total Cost
$487,500
Indirect Cost
$237,500
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Pasqual, Giulia; Chudnovskiy, Aleksey; Tas, Jeroen M J et al. (2018) Monitoring T cell-dendritic cell interactions in vivo by intercellular enzymatic labelling. Nature 553:496-500
Ersching, Jonatan; Efeyan, Alejo; Mesin, Luka et al. (2017) Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase. Immunity 46:1045-1058.e6
Kalaitzidis, Demetrios; Lee, Dongjun; Efeyan, Alejo et al. (2017) Amino acid-insensitive mTORC1 regulation enables nutritional stress resilience in hematopoietic stem cells. J Clin Invest 127:1405-1413
Mesin, Luka; Ersching, Jonatan; Victora, Gabriel D (2016) Germinal Center B Cell Dynamics. Immunity 45:471-482
Tas, Jeroen M J; Mesin, Luka; Pasqual, Giulia et al. (2016) Visualizing antibody affinity maturation in germinal centers. Science 351:1048-54
Bannard, Oliver; McGowan, Simon J; Ersching, Jonatan et al. (2016) Ubiquitin-mediated fluctuations in MHC class II facilitate efficient germinal center B cell responses. J Exp Med 213:993-1009
Bilate, Angelina M; Bousbaine, Djenet; Mesin, Luka et al. (2016) Tissue-specific emergence of regulatory and intraepithelial T cells from a clonal T cell precursor. Sci Immunol 1:eaaf7471
Victora, Gabriel D; Wilson, Patrick C (2015) Germinal center selection and the antibody response to influenza. Cell 163:545-8
Wang, Haikun; Geng, Jianlin; Wen, Xiaomin et al. (2014) The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells. Nat Immunol 15:667-75
Victora, Gabriel D; Mesin, Luka (2014) Clonal and cellular dynamics in germinal centers. Curr Opin Immunol 28:90-6

Showing the most recent 10 out of 11 publications