Single-cell transcriptomic analysis of allergen-specific T cells in allergy and asthma

CD4⁺ T helper (T_H) cells and regulatory T (T_reg) cells that respond to common allergens play an important role in driving and dampening airway inflammation in patients with asthma. Until recently, direct, unbiased molecular analysis of allergen-reactive T_H and T_reg cells has not been possible. To better understand the diversity of these T cell subsets in allergy and asthma, we analyzed the single-cell transcriptome of ~50,000 house dust mite (HDM) allergen-reactive T_H cells and T_reg cells from asthmatics with HDM allergy and from three control groups: asthmatics without HDM allergy and nonasthmatics with and without HDM allergy. Our analyses show that HDM allergen-reactive T_H and T_reg cells are highly heterogeneous and certain subsets are quantitatively and qualitatively different in individuals with HDM-reactive asthma. The number of interleukin-9 (IL-9)-expressing HDM-reactive T_H cells is greater in asthmatics with HDM allergy compared with nonasthmatics with HDM allergy, and this IL-9-expressing T_H subset displays enhanced pathogenic properties. More HDM-reactive T_H and T_reg cells expressing the interferon response signature (T_HIFNR and T_regIFNR) are present in asthmatics without HDM allergy compared with those with HDM allergy. In cells from these subsets (T_HIFNR and T_regIFNR), expression of TNFSF10 was enriched; its product, tumor necrosis factor-related apoptosis-inducing ligand, dampens activation of T_H cells. These findings suggest that the T_HIFNR and T_regIFNR subsets may dampen allergic responses, which may help explain why only some people develop T_H2 responses to nearly ubiquitous allergens.