Memory T Cells in Respiratory Virus Infections: Protective Potential and Persistent Vulnerabilities

Abstract

Respiratory virus infections, such as those caused by influenza viruses, respiratory syncytial virus (RSV), and coronaviruses, pose a significant global health burden. While the immune system's adaptive components, including memory T cells, are critical for recognizing and combating these pathogens, recurrent infections and variable disease outcomes persist. Memory T cells are a key element of long-term immunity, capable of responding swiftly upon re-exposure to pathogens. They play diverse roles, including cross-reactivity to conserved viral epitopes and modulation of inflammatory responses. However, the protective efficacy of these cells is influenced by several factors, including viral evolution, host age, and immune system dynamics. This review explores the dichotomy of memory T cells in respiratory virus infections: their potential to confer robust protection and the limitations that allow for breakthrough infections. Understanding the underlying mechanisms governing the formation, maintenance, and functional deployment of memory T cells in respiratory mucosa is critical for improving immunological interventions. We highlight recent advances in vaccine strategies aimed at bolstering T cell-mediated immunity and discuss the challenges posed by viral immune evasion. Addressing these gaps in knowledge is pivotal for designing effective therapeutics and vaccines to mitigate the global burden of respiratory viruses.

Keywords: adaptive immunity; immunology; lymphocyte; memory T cells; viral infection.

Figure 1

The formation and role of memory T cells in lung infection and reinfection. Initially, dendritic cells detect airborne pathogens in the lung (Step 1) and migrate to the mediastinal lymph node (MLN) via the bloodstream (Step 2). In the MLN, dendritic cells present antigens to naïve T and B cells, leading to their activation and expansion into effector and memory cell populations, including CD4+ T cells, CD8+ T cells, and memory B cells (Step 3). Chemokines guide the activated immune cells back to the infected lung, allowing them to home to the site of infection (Step 4). Effector T cells and short-lived plasma cells clear the pathogen, reducing the infection (Step 5). Persistent inflammation and antigen presence can lead to the formation of inducible bronchus-associated lymphoid tissue (iBALT), which promotes the maintenance of resident memory B and T cells (Step 6). Over time, resident airway memory T cells (RAMD) accumulate and self-renew in the lung tissue, enabling a rapid and effective immune response upon reinfection (Step 7).

Figure 2

Mechanisms of viral evolution: antigenic shift and antigenic drift. On the left, “Antigenic Shift” shows the process where two different viruses (Virus A and Virus B) infect the same host cell and exchange genetic material, leading to the creation of a new hybrid virus (Virus C) with a mixed genome. This can result in a virus with a new antigenic profile, potentially leading to major outbreaks if the population has little to no immunity against it. On the right, “Antigenic Drift” describes a more gradual process where a single virus (Virus A) accumulates point mutations over time, resulting in small changes to its genome. This can gradually change the virus’s antigenic properties and may lead to seasonal flu variations as the immune system needs to continuously adapt to the new viral forms.