Asthma is a chronic inflammatory disease and is frequently associated with an allergic component. Asthma poses a major public health burden. Prevalence of this disease has increased greatly over the last four decades yet many questions regarding the basic mechanisms that lead to this disease remain unanswered. High-affinity, allergen-specific IgE antibodies are strongly implicated in the pathogenesis of allergic asthma, as are pathways involved in IgE production such as signaling by interleukin-4 (IL-4). A unique subset of CD4 T cells termed follicular helper T cells (Tfh cells) are present in the germinal center (GC) where they provide critical help in the production of high-affinity antibodies as well as isotype class switching, including to IgE, via production of IL-4. Tfh cells also secrete IL-21,a cytokine that represses switching to IgE, suggesting a complex relationship between Tfh cells, cytokine production, and isotype switching. This proposal seeks to test the hypothesis that Tfh cells regulate the production of IL-4 and IL-21 independently to coordinate the GC response and evoke IgE production.
Three specific aims are proposed to interrogate this hypothesis.
The first aim will investigate the relationship between Tfh cells and the humoral response in vivo by defining subpopulations of Tfh cells by their cytokine secretion on the basis of intracellular staining as well as using mutant mice expressing fluorescent reporter genes. The composition of these populations will be measured in relation to antibody titer and the GC response in several models of infection and immunization and across time and anatomical location.
The second aim i s to directly connect different subpopulations of cytokine-secreting Tfh cells with the GC B cells they are interacting with, and to utilize an adoptive transfer system to test the function of these individual populations. In the third aim, regulatory networks controlling cytokin production will be determined using advanced techniques in next-generation sequencing and computational biology. Altogether, this work will further clarify the mechanism by which Tfh cells control allergy- inducing IgE antibodies and in doing so will identify targets for disrupting this process. In addition, this application details the applicant's training plan including research mentorship, advanced coursework, training in new techniques, and development of skills in scientific professionalism, writing, and presentation of data. The development of new treatments for major diseases like asthma depends on projects like this one which translate clinical problems into basic research questions. The research and training outlined in this application will prepare the applicant to pursue a career in the conduct of clinically relevant research as an independent physician scientist.

Public Health Relevance

Asthma is a chronic inflammatory disease of the airway with a significant allergic component. Allergic asthma is characterized by the development of high levels of antibodies in response to environmental allergens, a process which involves collaboration between T and B cells. Identification of the steps involved in this process, as well as their molecular mechanisms, will aid in the development of new therapeutic strategies to treat asthma and other allergic diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30HL120497-01A1
Application #
8649583
Study Section
Special Emphasis Panel (ZRG1-F07-K (20))
Program Officer
Tigno, Xenia
Project Start
2014-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$47,232
Indirect Cost
Name
Yale University
Department
None
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520