House dust-mite allergen-specific T cell subsets in allergy and asthma

About This Grant

PROJECT SUMMARY One third of the population suffer from allergic diseases including asthma, rhinitis, atopic dermatitis and food allergy. House-dust mite (HDM) is the most common allergen with nearly ubiquitous presence in US homes and ~30% sensitization. It is an enigma why some people develop allergy to a ubiquitous allergen such as HDM while others don’t. HDM is also the most important allergen driving sensitization and risk of allergic diseases like asthma. But, again, only some people with HDM sensitization develop asthma and/or rhinitis, for unknown reasons. In this proposal, we will explore the mechanisms and cell types that drive either natural tolerance or allergen sensitization and the development of asthma. We focus on CD4+ helper T cells (TH) because of their importance in allergy and asthma. To determine the diversity of these TH cell subsets in allergy and asthma, we performed one of the first single-cell transcriptomic studies of HDM allergen-specific TH cells. We identified of a novel subset of HDM-specific TH cells characterized by an interferon response (IFNR) gene signature (THIFNR cells), which was negatively associated with HDM sensitization. In addition, HDM- specific TH2 cells with increased expression of IL9 were increased in HDM-sensitized subjects with asthma compared to those without asthma. Based on these findings, we hypothesize that HDM-specific THIFNR cells protect against HDM-sensitization, and IL9-expressing TH2 cells in the airways, specifically tissue-resident memory T cells (TRM cells) promote the development of HDM-allergic asthma. In Aim 1, we will determine the association between HDM-specific THIFNR cells and protection against HDM sensitization. We will assess subjects enrolled in the Isle of Wight Whole Population Birth Cohort (IOWBC; n=1456). We will identify subgroups of participants (n=140) with: (i) Persistent HDM-sensitization since childhood (ii) Never HDM- sensitization since childhood, (iii) Adult-onset HDM-sensitization, and (iv) Adult-onset HDM tolerance. Using longitudinally-collected peripheral blood mononuclear cells, we will isolate HDM-specific T cells and perform single-cell transcriptome and TCR-seq analysis to enumerate the frequency, properties, persistence and clonality of HDM-specific T cell subsets including the novel THIFNR cell subpopulation, and determine their association with protection against development of HDM-sensitization at different ages and with adult-onset tolerance. In Aim 2, we will identify HDM-specific T cell subsets in the blood and airways associated with the development of asthma in subjects with HDM-sensitization. We will enroll 125 subjects with HDM-allergy from the IOWBC (n=55 with asthma, n=70 without asthma), obtain blood and airway samples longitudinally collected, and in a subgroup following HDM-allergen bronchial challenge. We will perform single-cell transcriptome and TCR-seq analysis to determine the frequency, properties, persistence and clonality of HDM- specific TH cell and TRM subsets in the blood and airways, and their association with asthma development.