Asthma is an inflammatory disease of the airways characterized by acute, intermittent and recurrent episodes of inflammation that can be induced by a specific allergen. CD4+ T cells contribute to this process by producing the Type 2 cytokines IL-4, IL-5, and IL-13 and inducing B cell production of IgE in response to T cell receptor (TCR) recognition of allergen peptides bound to MHCII molecules on host cells. In both murine models of disease and asthmatic patients, quiescent allergen peptide:MHCII (pMHCII)-specific CD4+ memory T cells can persist in lungs and lymphoid organs long after resolution of inflammation. Upon subsequent exposure to allergen, CD4+ memory T cells rapidly drive asthma-induced immunopathology making these cells attractive targets for allergen-specific immune modulation. Little is known, however, about the differentiation and maintenance of Th2 cells that orchestrate the asthmatic response due to the challenge of tracking small populations of CD4+ T cells that express allergen pMHCII: specific TCRs. To address this lack of knowledge, we produced an MHCII tetramer containing a peptide from the Der p1 protein of the house dust mite (HDM), Dermatophagoides pteronyssinus, the most common cause of atopic asthma. Using this tetramer and a novel magnetic bead-based cell enrichment method of our design, we have found three allergen- specific CD4+ T cell subsets that develop after the induction of allergic airway inflammation. The central hypothesis of this application is that functionally heterogeneous yet synergistic populations of Th2 effector and memory cells develop in response to competition between lineage-defining transcription factors and underlies asthma pathogenesis. The goals of this proposal are to identify the molecular and cellular mechanisms that lead to Th2 effector cell heterogeneity and determine how these cells persist and contribute to asthma pathogenesis in the lung so they can be modified by immunotherapy. This innovative approach could provide the means for preventing allergenic priming of memory Th2 cells or eliminating them through antigen-specific therapies.

Public Health Relevance

Asthma is an inflammatory disease of the airways that affects more than 300 million people worldwide and is increasing in incidence. This research will focus on understanding the differentiation, function and maintenance of allergen-specific CD4+ T cells that orchestrate the asthmatic response to the most common cause of allergic asthma, house dust mite. These studies will provide novel mechanisms to develop therapies that prevent and inhibit allergen-induced asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI108626-01A1S1
Application #
8910831
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Davidson, Wendy F
Project Start
2014-02-01
Project End
2019-01-31
Budget Start
2014-08-15
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$57,791
Indirect Cost
$24,578
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Krishnamurty, Akshay T; Pepper, Marion (2014) Inflammatory interference of memory formation. Trends Immunol 35:355-7