Innate and adaptive immunity are both activated upon vaccination. We have recently demonstrated that the two adaptive immune arms (cellular and humoral immunity) are uniquely induced by different types of myeloid dendritic cell (DC) subsets. In particular, IL-12 induces the development of CD4+ T cells capable of helping B cells through the secretion of IL-21, a cytokine that potently promotes B cell growth, differentiation, and classswitching. These CD4-I- T cells share properties with T follicular helper cells (Tfh), a recently established specialized B cell-helper CD4-f T cell subset. Human Tfh cells can be found in the germinal centers of secondary lymphoid organs and in blood, and are characterized by the expression of the chemokine receptor CXCRS and the secretion of IL-21. Thus, Tfh cells appear to playa fundamental role in the developmentof antibody responses ? upon vaccination. However, little is known about how vaccines induce Tfh responses and how the induced Tfh cells regulate antibody responses. Our recent studies indicate that Tfh cells from human blood are composed of functionally distinct subsets. The main hypothesis of this project is that the differential mobilization of Tfh subsets dictates the quality and quantity of vaccine-induced humoral immunity. In particular, we hypothesize that a positive vaccine outcome is associated with activation of helper Tfh cells (i.e., Tfh2 and Tfhl7 cells). In contrast, a negative vaccine outcome is associated with either a defect of helper Tfh cell activation or an overactivation of suppressor Tfh cells, i.e., Tfhl cells. In this Project, we will establish the molecular signatures of blood Tfh cells and their functionally different components at baseline, and upon activation following Flu vaccination. The ultimate goal of this Project is to generate tools that will permit high fidelity assessment of in vivo activation of Tfh subsets and prediction of protective responses to vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI089987-04
Application #
8501326
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$200,936
Indirect Cost
$44,402
Name
Baylor Research Institute
Department
Type
DUNS #
145745022
City
Dallas
State
TX
Country
United States
Zip Code
75204
Heinonen, Santtu; Jartti, Tuomas; Garcia, Carla et al. (2016) Rhinovirus Detection in Symptomatic and Asymptomatic Children: Value of Host Transcriptome Analysis. Am J Respir Crit Care Med 193:772-82
Schmitt, Nathalie; Liu, Yang; Bentebibel, Salah-Eddine et al. (2016) Molecular Mechanisms Regulating T Helper 1 versus T Follicular Helper Cell Differentiation in Humans. Cell Rep 16:1082-95
Bentebibel, Salah-Eddine; Khurana, Surender; Schmitt, Nathalie et al. (2016) ICOS(+)PD-1(+)CXCR3(+) T follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination. Sci Rep 6:26494
de Steenhuijsen Piters, Wouter A A; Heinonen, Santtu; Hasrat, Raiza et al. (2016) Nasopharyngeal Microbiota, Host Transcriptome, and Disease Severity in Children with Respiratory Syncytial Virus Infection. Am J Respir Crit Care Med 194:1104-1115
Blohmke, Christoph J; Darton, Thomas C; Jones, Claire et al. (2016) Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever. J Exp Med 213:1061-77
Sandoval, Carmen; Barrera, Aldo; Ferrés, Marcela et al. (2016) Infection in Health Personnel with High and Low Levels of Exposure in a Hospital Setting during the H1N1 2009 Influenza A Pandemic. PLoS One 11:e0147271
Ueno, Hideki; Banchereau, Jacques; Vinuesa, Carola G (2015) Pathophysiology of T follicular helper cells in humans and mice. Nat Immunol 16:142-52
Schmitt, Nathalie; Ueno, Hideki (2015) Regulation of human helper T cell subset differentiation by cytokines. Curr Opin Immunol 34:130-6
Turner, Jacob A; Bolen, Christopher R; Blankenship, Derek M (2015) Quantitative gene set analysis generalized for repeated measures, confounder adjustment, and continuous covariates. BMC Bioinformatics 16:272
Zitvogel, Laurence; Galluzzi, Lorenzo; Viaud, Sophie et al. (2015) Cancer and the gut microbiota: an unexpected link. Sci Transl Med 7:271ps1

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