Targeting Multiple Costimulatory Molecules Prevents Persistence of Lung Tissue-resident Memory T cells and Leads to Airway Tolerance
Year: 2023
Type: conference-abstract
Abstract: Pools of tissue-resident memory T (Trm) cells are thought to maintain and contribute to exacerbations of inflammatory or autoimmune disease. We hypothesized that several costimulatory molecules would control the expansion and maintenance of these populations when responding to antigen, and tested the potential of targeting OX40L, CD30L, and ICOSL, using a house dust mite (HDM) allergen-based mouse model of asthmatic lung inflammation. We found that allergen induced persisting CD4+CD44hiCD62Llo CD69+ and CD69− lung-localized Trm cells and RNA-seq revealed the heterogeneity of these memory pools, containing Th2, Tfh, Th17, and Th1 clusters. Showing their reliance on costimulation for recall activity to allergen, blocking CD30L and OX40L together, or blocking ICOSL alone, resulted in ~50% reduction in the expansion of both CD69+ and CD69− tissue-resident effector T cells during a secondary allergen exposure or a tertiary allergen exposure. Blocking all three molecules at once further inhibited T cell accumulation by ~90%, corresponding to a similar reduction in lung tissue inflammation, including eosinophilia. Moreover, triple costimulation blockade resulted in a diminished persisting lung tissue-resident memory T cell pool, which failed to expand to normal levels and drive further exacerbations of lung inflammation upon subsequent exposure to allergen, resulting in a state of airway tolerance. Overall, our data suggest that the concurrent inhibition of OX40, CD30, and ICOS signaling, can impair the expansion and persistence of lung-localized Trm cells and could engender long-lasting tolerance in asthma and similar autoimmune or inflammatory diseases that are maintained by tissue-resident memory T cells.
Source: The Journal of Immunology
Authors: Gurupreet Singh Sethi, Michael Croft
Institution: La Jolla Institute for Immunology
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4385685361