Lung-Resident Memory T Cells and Epithelial Antigen Presentation Drive Neutrophilic Asthma: A Pathway for Targeted Therapy

Asthma is a chronic and often debilitating respiratory disease that affects over 350 million people worldwide, posing a significant public health challenge. It is broadly categorized into eosinophilic and neutrophilic asthma, each driven by distinct immune pathways and requiring different treatment strategies. While eosinophilic asthma, primarily mediated by T helper 2 (TH2) cells, has been extensively studied and responds well to corticosteroids, neutrophilic asthma remains poorly understood and often resists standard therapies. This severe and treatment-refractory form of asthma disproportionately affects adults and is associated with persistent inflammation, lung tissue damage, and poor disease prognosis. One of the key barriers to advancing research and treatment for neutrophilic asthma is the lack of reliable animal models that accurately mimic its human counterpart. Traditional murine models of allergic airway disease predominantly induce eosinophilic inflammation and fail to recapitulate the steroid-resistant neutrophilic response observed in patients. Moreover, previous attempts to enhance neutrophilic inflammation in these models have often relied on artificial adjuvants or bacterial components, which may not reflect the natural pathogenesis of the disease in humans. To address this gap, new research paper by Cell Reports and conducted by researchers from University of Michigan Medical School led by Professor Anukul Shenoy in collaboration with researchers at Boston University Chobanian & Avedisian School of Medicine led by Professor  Joseph Mizgerd developed a more physiologically relevant model of neutrophilic asthma by repeatedly exposing sensitized mice to inhaled allergens over time. This approach allowed them to investigate how recurrent allergen exposure reshapes lung immune responses and predisposes individuals to severe, neutrophil-dominated airway inflammation. By closely mimicking the gradual environmental exposures that contribute to asthma progression in humans, this model offers new insights into the cellular and molecular mechanisms underlying neutrophilic asthma.

One of the study’s major findings is the identification of an unconventional subset of lung-resident memory CD4+ T (TRM) cells that play a central role in driving neutrophilic inflammation. Unlike classical TH17 cells, which are known to produce interleukin (IL)-17A and promote neutrophil recruitment, these TRM cells exhibit low expression of the TH17-defining transcription factor RORγt. Nevertheless, they remain potent producers of IL-17A, which, in turn, stimulates airway epithelial cells to secrete CXCL5, a key chemokine that attracts neutrophils into the airways. This previously unrecognized “epithelium-lymphocyte-neutrophil” communication network provides a new framework for understanding how allergic inflammation transitions from eosinophilic to neutrophilic in certain patients. Furthermore, the study highlights the critical role of epithelial antigen presentation in regulating the fate and function of lung TRM cells. Specifically, airway secretory cells expressing MUC5AC—typically associated with mucus overproduction in asthma—also function as antigen-presenting cells, influencing the differentiation of TRM cells into either TH1 or TH2 subsets. By presenting antigens via MHC class II molecules, these epithelial cells help maintain immune balance and suppress excessive neutrophilic inflammation. However, when this regulatory function is disrupted, unchecked IL-17A-driven neutrophil recruitment can lead to severe airway damage.

The researchers designed their experiments to closely mimic the chronic exposure patterns that asthma patients experience in real life. Instead of relying on single, high-dose allergen challenges that typically induce eosinophilic inflammation in mice, they opted for a more gradual and repeated allergen exposure model. By sensitizing the mice to house dust mite (HDM) extract and exposing them repeatedly over time, they observed a distinct shift in immune responses. Unlike conventional models that primarily recruit eosinophils to the lungs, this approach led to a more robust neutrophilic inflammation, mirroring the treatment-resistant form of asthma seen in many patients. One of their most striking findings emerged when they analyzed the immune cell populations within the lung tissue. They discovered an unusual subset of lung-resident memory CD4+ T (TRM) cells that were not previously associated with neutrophilic inflammation. These cells, despite lacking the classical TH17 marker RORγt, were potent producers of IL-17A, a cytokine well known for its role in neutrophil recruitment. This was an unexpected result, as it suggested that IL-17A production in the lung could originate from a previously uncharacterized T cell population rather than from conventional TH17 cells. The researchers confirmed this by selectively depleting these TRM cells, which led to a marked reduction in neutrophil accumulation in the airways, further validating their critical role in disease progression. To understand how these TRM cells orchestrate neutrophilic inflammation, the researchers turned their attention to airway epithelial cells. They hypothesized that these epithelial cells might be acting as more than just a physical barrier and instead playing an active role in immune signaling. Through genetic analysis and immunostaining, they found that a subset of epithelial cells expressing MUC5AC—a mucin protein commonly linked to excessive mucus production in asthma—were also expressing MHC class II molecules. This indicated that these cells had antigen-presenting capabilities, allowing them to influence the differentiation and activity of TRM cells. In other words, the same cells responsible for airway mucus production were also shaping immune responses, a dual role that had not been fully appreciated before. To further explore this connection, they engineered mice that lacked MHC class II expression specifically in airway epithelial cells. Remarkably, these mice exhibited a dramatic reduction in neutrophilic inflammation despite repeated allergen exposures. This finding provided strong evidence that epithelial antigen presentation was a key factor in the persistence of neutrophilic asthma. Without this antigen presentation, TRM cells failed to sustain their IL-17A production, leading to a decrease in neutrophil-recruiting signals like CXCL5. This experiment not only confirmed the role of epithelial cells in shaping immune responses but also suggested that targeting this interaction could be a novel therapeutic strategy. Given the strong link between IL-17A and neutrophil recruitment, the team explored whether they could counteract this pathway using a well-known immune modulator: interferon-gamma (IFN-γ). IFN-γ is typically associated with TH1-driven immune responses and is known to suppress IL-17A activity in other inflammatory conditions. To test its effect, they administered recombinant IFN-γ to mice exposed to repeated allergen challenges. The results were striking—treated mice displayed a significant reduction in CXCL5 levels, leading to fewer neutrophils infiltrating the lungs. Not only did this intervention dampen airway inflammation, but it also improved overall lung function, suggesting that boosting IFN-γ activity could be a viable therapeutic approach for patients with severe neutrophilic asthma. Additionally, the authors examined whether the presence of IFN-γ could alter the composition of lung TRM cells. They found that increasing IFN-γ levels prompted a shift in TRM cell behavior, reducing their IL-17A production and making them more similar to regulatory or TH1-like cells. This suggested that TRM cells were not irreversibly committed to a neutrophilic inflammatory state but could be functionally reprogrammed under the right conditions.

In conclusion, the researchers have identified a critical pathway that could be targeted for therapeutic intervention. Traditional asthma treatments, including corticosteroids, primarily aim to suppress eosinophilic inflammation, leaving patients with neutrophil-dominant disease without effective options. This study provides a compelling explanation for why these therapies fail and offers a new direction for treatment development. Moreover, the discovery that airway epithelial cells are not just passive barriers but active participants in immune regulation. By demonstrating that these cells present antigens and influence the behavior of TRM cells, the researchers have opened up a new avenue for therapeutic strategies. If this antigen-presenting function can be blocked or modified, it may be possible to prevent the persistent cycle of inflammation that characterizes severe asthma. This insight also raises broader questions about the role of epithelial cells in other chronic inflammatory diseases, suggesting that similar mechanisms could be at play in conditions such as chronic obstructive pulmonary disease (COPD) or cystic fibrosis. Furthermore, the potential for immune reprogramming as a treatment approach. The study’s findings suggest that TRM cells, which were previously thought to be locked into an inflammatory state, can be shifted towards a more balanced or regulatory phenotype by increasing interferon-gamma (IFN-γ) activity. This discovery is particularly exciting because it suggests that instead of simply suppressing inflammation, future therapies could focus on guiding the immune system toward a healthier equilibrium. If similar immune modulation strategies prove successful in human trials, they could provide long-lasting relief for asthma patients without the broad immunosuppressive effects associated with current treatments.