Function and Differentiation

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Project Summary/Abstract 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 function and maintenance of Th2 memory 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 that IL-2 dependent, functionally heterogeneous populations of Th2 tissue resident memory cells reside in the lung for long periods of time. The central hypothesis of this application is that these distinct yet synergistic populations of Th2 “effector Trm” and B cell helping “Tfh Trm” contribute to asthma pathogenesis in unique ways. The goals of this proposal are to identify the molecular and cellular mechanisms that lead to Th2 Trm cell heterogeneity and determine how these cells persist in different regions of the lung. This innovative approach could provide the means for targeting specific pathologic functions of memory Th2 cells by immunotherapy or eliminating them altogether.