Defining how memory T helper type 2 (Th2) cells initiate a recall response to an aeroallergen has the potential to change our therapeutic approach to allergic asthma, the most common asthma subtype. During periods of disease quiescence, approximately 5-10% of effector Th2 cells driving allergic asthma give rise to long-lived memory cells that are poised to respond upon allergen re-exposure. Consequently, targeting memory Th2 cell activation is an attractive therapeutic strategy. However, it is not well understood how allergen inhalation initiates a memory Th2 cell response. Recently, a new paradigm in memory T cell biology has emerged in which tissue-resident memory T cells (Trm) persisting in non-lymphoid tissue rapidly initiate recall responses. While tissue-resident memory Th2 cells (Th2-Trm) have been described, the function of this population in promoting allergic inflammation is unclear. The objective of this proposal is to define the mechanisms whereby Th2-Trm persisting in the lung orchestrate a recall response to an inhaled allergen. Our central hypothesis is that Th2-Trm ignite allergic airway inflammation via a rapid and enhanced response to cognate antigen and the ability to recruit circulating Th2 cells to the sites of antigen presentation. Mechanistically, we hypothesize that Th2-Trm co-localize with dendritic cells (DCs) expressing the Th2 cell-attracting chemokine CCL17 and after allergen re-challenge rapidly produce type 2 cytokines that initiate allergic inflammation and markedly induce DC expression of CCL17. This enhanced CCL17 expression recruits circulating Th2 cells from the blood to sites of antigen presentation where they are activated, amplifying allergic inflammation. We propose to use innovative experimental systems to define the function of Th2-Trm, including parabiosis of allergen-treated and nave mice, a novel CCL17/CCL22 reporter mouse as well as single cell RNA-seq analysis of airway mucosal T cells from humans with allergic asthma. Specifically, we propose (1) To define the function of Th2-Trm in regulating recurrent allergic airway inflammation and (2) To define the role of CCL17 in regulating Th2-Trm localization and function. Dr. Rahimi will perform the work in this K08 proposal in the Center for Immunology and Inflammatory diseases (CIID) at Massachusetts General Hospital (MGH) under the mentorship of Dr. Andrew Luster. The CIID is a state-of-the-art multidisciplinary research center focused on mechanisms of immune-mediated inflammatory diseases and is the foundation for immunology research at MGH. Dr. Rahimi has developed a career development plan consisting of coursework in advanced microscopy, bioinformatics and human translational research as well as organized a Training Advisory Committee to provide expertise and assistance in these areas. The goal of this K08 award is to provide Dr. Rahimi with the intellectual and technical training to become an independent, R01-funded investigator with expertise in the immunologic mechanisms driving allergic asthma and other chronic eosinophilic lung diseases.

Public Health Relevance

Memory CD4+ T helper type 2 (Th2) cells are critical in promoting allergic asthma, the most common asthma endotype. This application proposes a research strategy to define the function of lung-resident memory Th2 cells in driving recurrent allergic airway inflammation. The successful completion of the proposed studies has the potential to focus new asthma therapies on specifically targeting the biology of lung-resident memory Th2 cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL140173-01
Application #
9431929
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Tigno, Xenia
Project Start
2017-12-08
Project End
2022-12-06
Budget Start
2017-12-08
Budget End
2018-12-06
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114