Lung-Resident Memory Th2 cells in Asthma: New Therapeutic Targets

Massachusetts General Hospital, Boston MA

Investigators

Abstract

Asthma is one of the most common chronic diseases and it is still on the rise with a prevalence estimated at 8- 9% of the U.S. population (~40 million) with an estimated cost of $50 billion/year in the US. The long-term goal of this project is to develop new therapeutic approaches to asthma treatment that offer the potential for a long- lasting cure, instead of merely suppressing chronic lung inflammation. Allergic asthma is the most common asthma endotype and is thought to be driven in large part by a type 2 airway immune response to inhaled allergens. Memory CD4+ T helper type 2 (Th2) cells initiate a recall type 2 immune response to aeroallergens driving recurrent asthma exacerbations. A new paradigm in memory T cell biology has emerged in which tissue- resident memory T cells (Trm) persisting in non-lymphoid tissue are critical for initiating tissue antigen-specific recall responses. Trm are a distinct subset of memory T cells that are anatomically positioned and transcriptionally programmed to initiate the tissue amnestic response to antigen. We and others have found that Th2-Trm in the lung are the relevant allergen-specific Th2 cell subset that uniquely drives the cardinal features of allergic asthma upon allergen rechallenge. The persistence of Th2-Trm in the lung drive recurrent asthma exacerbations despite current therapies that target their mediators. The overall objective of this project is to identify key pathways that mediate the survival and maintenance of Th2-Trm in specialized niches in the asthmatic lung. Th2-Trm possess unique properties including increased expression of effector molecules and specific adhesion and chemokine receptors, such as CXCR6. The central hypothesis of this proposal is that the CXCR6 chemokine system positions Th2 cells in proximity to cells that supply survival signals for the maintenance of allergen-specific resident memory Th2 cells in the allergic lung. Based on our preliminary data, we hypothesize that interleukin-7 (IL7) and CCL21 produced by lymphatic endothelial cells along with CXCL16 produced by CCR7+DCs establishes a niche that provides survival signals for Th2-Trm in the lung. We also hypothesize that inhibiting the CXCR6 chemokine system could be a new therapeutic strategy to treat allergic asthma. We will explore these hypotheses in the following 3 specific aims: (1) To define the role of CXCR6 in the generation and/or maintenance of allergen-specific Th2-Trm in the allergic lung; (2) To determine if inhibiting the CXCR6 ligand, CXCL16, in the memory phase will decrease lung Th2-Trm and attenuate the recall response to allergen and allergic airway inflammation; and (3) To define the critical survival factors in the lung niche for the maintenance of Th2-Trm in the memory phase and extent our observations to human asthma. The proposed research is innovative as it focuses on a novel, potentially curative approach to asthma treatment grounded in new biology that will be explored using novel strains of mice and spatial transcriptomics of human asthmatic lungs. These studies are significant as they will define the role of CXCR6 in Th2-Trm biology and determine if inhibiting this chemokine system is a viable new therapeutic approach to cure chronic allergic asthma.