T Cell Responses in Respiratory Viral Infections and Chronic Obstructive Pulmonary Disease

Respiratory viral infections are among the most common diseases worldwide, causing significant morbidity and mortality. These infections, often referred to as the “common cold,” flu, bronchiolitis, and pneumonia, result in approximately 200 million cases of viral pneumonia annually. Chronic obstructive pulmonary disease (COPD), a major global health concern, is characterized by persistent airflow limitation and is the third leading cause of death worldwide. The interplay between respiratory viral infections and COPD exacerbates disease severity, leading to increased healthcare burdens. This review critically examines the role of T cells in respiratory viral infections and COPD, focusing on their activation, effector functions, and regulatory mechanisms.

Introduction

Respiratory viral infections and COPD are closely intertwined, with viral infections often triggering acute exacerbations of COPD (AECOPD). The immune response to respiratory viruses involves both innate and adaptive immunity, with T cells playing a pivotal role in viral clearance and inflammation regulation. However, an excessive immune response can lead to tissue damage, cytokine storms, and chronic inflammation, complicating disease management. This review explores the dual role of T cells in providing protection against viral infections and contributing to the pathogenesis of COPD.

Comorbidity and Innate Immune Responses in Respiratory Viral Infections and COPD

Respiratory viral infections are a significant trigger for AECOPD, with viral genetic elements detected in approximately half of all AECOPD cases. Human rhinovirus (HRV) is the most commonly detected virus, present in 12% to 63% of cases. Other viruses, such as respiratory syncytial virus (RSV), influenza virus, and coronavirus, also contribute to COPD exacerbations. The innate immune response, involving airway epithelial cells, macrophages, and dendritic cells, plays a crucial role in initiating and regulating T cell responses. Pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) from viruses, leading to the production of cytokines and chemokines that recruit immune cells to the site of infection.

T Cell Responses in Respiratory Viral Infections and COPD

T cells are activated through three primary mechanisms: antigen presentation, co-stimulation or co-inhibition, and cytokine stimulation. Antigen presentation involves the recognition of viral peptides by T cell receptors (TCRs) on CD4+ and CD8+ T cells. Co-stimulatory molecules such as CD80/CD86 on antigen-presenting cells (APCs) interact with CD28 on T cells to enhance activation, while inhibitory molecules like CTLA-4 dampen T cell responses. Cytokines such as IL-33 and IL-2 further modulate T cell activation and differentiation.

CD8+ T Cells

CD8+ T cells are critical for controlling intracellular viral infections through cytolytic effector functions. Upon activation, CD8+ T cells upregulate cytolytic markers such as CD107a (LAMP1) and produce cytokines like IFN-γ and TNF-α, which enhance viral clearance. Memory CD8+ T cells, including tissue-resident memory T (TRM) cells, provide long-term protection against reinfection. However, persistent activation of CD8+ T cells in COPD patients is associated with disease progression and reduced lung function, highlighting their potential role in immunopathology.

CD4+ T Cells

CD4+ T cells play diverse roles in regulating immune responses to respiratory viruses. Helper CD4+ T cells (Th1, Th2, Th17) and regulatory T cells (Tregs) modulate B cell differentiation, antibody production, and CD8+ T cell activation. Th1 cells produce IFN-γ and TNF-α, which enhance antiviral immunity, while Th2 and Th17 cells contribute to inflammation and tissue damage. Tregs suppress excessive immune responses, preventing immunopathology. However, in COPD, autoreactive CD4+ T cells responding to self-antigens like elastin contribute to disease pathogenesis.

Mechanisms of T Cell Activation and Regulation

Antigen Presentation and Co-stimulation

Antigen presentation by APCs is a critical step in T cell activation. Viral peptides presented by HLA class I and II molecules on APCs are recognized by CD8+ and CD4+ T cells, respectively. Co-stimulatory interactions between APCs and T cells, such as CD80/CD86-CD28, enhance T cell activation, while inhibitory interactions, such as PD-1-PD-L1, dampen T cell responses. Cytokine stimulation further modulates T cell activation and differentiation, with IL-2 promoting T cell proliferation and IL-33 enhancing Th2 responses.

Cytokine Regulation

Cytokines play a central role in shaping T cell responses. IFN-γ and TNF-α produced by Th1 cells enhance antiviral immunity, while IL-4, IL-5, and IL-13 produced by Th2 cells contribute to inflammation and tissue damage. IL-17 and IL-22 produced by Th17 cells recruit neutrophils and exacerbate inflammation. Tregs produce IL-10 and TGF-β, which suppress excessive immune responses and prevent immunopathology.

Memory T Cell Responses

Memory T cells, including central memory (TCM), effector memory (TEM), and tissue-resident memory (TRM) cells, provide long-term protection against reinfection. TRM cells localized in the lung parenchyma rapidly respond to reinfection, producing cytokines and cytolytic molecules to clear the virus. Cross-reactive memory T cells provide heterosubtypic protection against different strains of respiratory viruses, as demonstrated in influenza infection.

T Cell Dysfunction in COPD

In COPD, T cells exhibit functional alterations that contribute to disease pathogenesis. CD8+ T cells show increased cytolytic activity and IL-17 production, which are associated with lung tissue destruction. CD4+ T cells exhibit autoreactivity to self-antigens like elastin, leading to chronic inflammation. Tregs are reduced in COPD patients, leading to impaired suppression of inflammatory responses. These dysregulated T cell responses exacerbate COPD severity and contribute to disease progression.

Therapeutic Implications

Understanding the role of T cells in respiratory viral infections and COPD provides insights into potential therapeutic targets. Strategies to enhance antiviral T cell responses while dampening excessive inflammation could improve disease outcomes. Vaccination strategies that induce robust memory T cell responses, particularly TRM cells, could provide long-term protection against respiratory viruses. Targeting T cell regulatory pathways, such as PD-1-PD-L1 and CTLA-4, could modulate T cell responses and prevent immunopathology in COPD.

Conclusion

T cells play a dual role in respiratory viral infections and COPD, providing protection against viral infections while contributing to disease pathogenesis. The activation, effector functions, and regulation of T cells are critical for controlling viral infections and modulating inflammation. Dysregulated T cell responses in COPD exacerbate disease severity, highlighting the need for targeted therapeutic interventions. Future research should focus on understanding the precise mechanisms of T cell activation and regulation in respiratory viral infections and COPD to develop effective treatments and vaccines.

doi.org/10.1097/CM9.0000000000001388

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