Mechanisms of Immune Interference Between Respiratory Allergic Inflammation and Antiviral Immunity

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

Respiratory infections remain a major global health burden, and their severity is often exacerbated in individuals with chronic airway diseases such as allergic asthma. As such, allergic asthma is a well-established risk factor for hospitalization due to seasonal influenza, with asthmatic individuals more likely to require intensive care than non-asthmatics. Consistent with this, during the 2009 H1N1 influenza pandemic, asthma was one of the most common underlying comorbidities associated with increased hospitalizations. While it is widely recognized that asthma worsens the outcome of respiratory infections, the underlying immunological mechanisms remain poorly understood. In this FY2025project, we are investigating how chronic allergic airway inflammation alters influenza-specific immunity. To address this question, in FY2025 we developed a novel experimental approach that sequentially combines physiologically relevant models of asthma and influenza infection in mice. This system enables us to directly test how chronic allergic inflammation impacts the development of influenza-specific immune responses. Using this approach, we found that, similar to asthmatic individuals, allergic mice displayed impaired heterosubtypic protection against influenza virus —the ability to mount protective immune responses against different influenza virus strains not previously encountered. This compromised immunity was not due to differences in neutralizing antibody titers or the generation of circulating influenza-specific memory CD8⁺ T cells. Instead, the primary defect lay in the failure to generate influenza-specific, cross-reactive lung-resident memory CD8⁺ T cells (CD8⁺ TRMs). This observation is highly significant because CD8⁺ TRMs are a specialized subset of memory T cells that permanently reside in peripheral tissues such as the lung, where they serve as front-line sentinels. Unlike circulating memory T cells, TRMs can rapidly respond at the site of pathogen entry by producing antiviral cytokines (e.g., IFN-γ), exerting cytotoxic functions, and recruiting additional immune cells to control viral replication. Importantly, they recognize conserved viral epitopes, providing cross-protection against heterologous strains—a feature critical for heterosubtypic immunity to influenza. Through adoptive transfer and functional analyses, we determined that the TRM defect observed in allergic mice was not a consequence of impaired recruitment or maintenance in the lung, but rather originated much earlier—during the initial priming phase in the lung-draining lymph node. Specifically, allergic inflammation altered the microenvironment of the lung-draining lymph node in a way that disrupted the early programming of virus-specific CD8⁺ T cells. This misprogramming impaired the generation of TRM precursors capable of seeding the lung tissue. Mechanistically, elevated IL-6 signaling was identified as a critical driver of this defect. During primary infection, allergic mice exhibited increased IL-6 levels in the lung-draining lymph node, which interfered with the transcriptional programming of CD8⁺ T cells by suppressing CD25 and Blimp-1 expression—two factors essential for TRM differentiation. Importantly, genetic ablation of IL-6 restored CD25 and Blimp-1 expression in TRM precursors and fully rescued the formation of lung CD8⁺ TRM in allergic mice. These findings have two important implications. First, they identify a previously unrecognized lymph node–initiated signaling pathway—centered on IL-6—that critically influences the development of CD8⁺ TRM precursors. Second, they provide a mechanistic explanation for how ongoing allergic inflammation disrupts the establishment of heterosubtypic immunity. By interfering with early fate decisions in the lung-draining lymph node, chronic allergic inflammation undermines the generation of protective tissue-resident memory, even in the presence of robust systemic responses. As part of our FY2025 efforts, we are also investigating the role of lung-resident memory B cells (BRMs) in respiratory allergic responses and respiratory infections. This project builds upon our previously published work (Immunity, 2023), which demonstrated that BRMs are critical for influenza protection in the lung. In that study, we showed that influenza-specific BRMs are generated in response to IFN-γ and rapidly differentiate into plasma cells upon pulmonary rechallenge, producing pathogen-specific neutralizing antibodies that are essential for protection following influenza virus reinfection. Despite their established role in antiviral and antibacterial defense, the function of BRMs in the context of respiratory allergy remains poorly understood. Specifically, it is unclear whether BRMs mediate protective or pathogenic B cell responses following allergen re-exposure. The mechanisms that regulate allergen-specific BRM responses are also unknown—particularly given their reliance on IFN-γ, a cytokine that is minimally produced in the context of allergic inflammation. To address this gap, we are characterizing how allergen-specific BRMs are generated and maintained in the lung, how environmental factors—such as LPS exposure—affect their development, and how the crosstalk between allergy and viral infection influences BRM precursor differentiation. As part of these efforts, we initiated a collaboration with Dr. John O’Shea (NIAMS) to investigate how prolonged activation of different STAT signaling pathways impacts BRM differentiation. By integrating this work with our ongoing studies on TRMs, we aim to elucidate the factors that balance protective versus pathogenic tissue memory in the lung and evaluate the therapeutic potential of targeting these cells to prevent allergic reactions. Collectively, these studies will provide critical insight into how tissue-resident memory lymphocytes are shaped by allergic inflammation and infection.