Researchers from the University of Cambridge investigated how adenoid nasal-associated lymphoid tissue (NALT) responds to SARS-CoV-2 infection in adults. This tissue, located in the adenoid region, plays a crucial role in the immune defense of the upper respiratory tract, but its response to viral infections in adults has remained largely unexplored.
In children, germinal centers (GC) in NALT activate, where B-cells undergo maturation and produce antibodies. However, in adults, particularly those with severe COVID-19, GC formation in lymphoid organs such as the spleen and lymph nodes is nearly absent.
To understand the cellular and molecular adaptations that protect secondary lymphoid tissue in adults, researchers analyzed NALT samples from individuals who had recovered from COVID-19. The study included 23 participants:
- 10 healthy individuals as the control group;
- 8 patients with acute COVID-19 (one week after the first positive test);
- 5 recovering COVID-19 patients (3–5 weeks after the first positive test).
Mononuclear Phagocytes Contribute to NALT Protection and Repair
During acute COVID-19, NALT increased in classical monocytes, which secreted chemokines that attracted neutrophils. In acute and recovering COVID-19 patients, classical monocytes exhibited increased mRNA production of S100A8/9 genes. The S100A8/9 proteins form calprotectin, which binds metal ions and deprives bacteria in the respiratory tract, including staphylococci, of essential micronutrients. Additionally, inflammatory (monocytic) dendritic cells (moDCs) were present in NALT, which actively recruited neutrophils instead of presenting antigens.
Coronavirus directly infects respiratory epithelium. Accordingly, the SARS-CoV-2 spike protein was detected in epithelial cells and some subepithelial T-cells. In acute COVID-19, CD14 monocytes were predominantly localized in the subepithelium. In recovering patients, CD14 monocytes formed a shield around B-cell follicles. Neutrophils were also present in epithelial and subepithelial areas, forming neutrophil extracellular traps (NETs) that bind and kill invading bacteria. Thus, monocytes producing calprotectin and neutrophils creating NETs may work together to protect lymphoid tissues following epithelial cell damage caused by viral invasion.
Recovering patients’ NALT exhibited an increased number of macrophages. Compared to acute COVID-19 patients, recovering macrophages showed higher IL-18 production.
During acute COVID-19, compared to the control group, macrophages and dendritic cells in NALT exhibited heightened activity of genes associated with type I and type II interferon (IFN-α and IFN-γ) responses. In recovering patients, IFN response gene activity was less prominent in dendritic cells but persisted in macrophages. Additionally, macrophages in recovering patients exhibited increased expression of genes linked to epithelial-mesenchymal transition, aligning with macrophages’ role in tissue homeostasis restoration.
During acute COVID-19, monocytes and monocytic dendritic cells produce chemokines that attract neutrophils, amplifying inflammation and creating a self-sustaining inflammatory cycle. These cells accumulate at the NALT periphery, forming a protective barrier.
In recovering patients, NALT macrophages increased, predominantly residing in the T-cell zone and including a FOLR2-positive subset. These macrophages contribute to tissue repair, maintaining structural integrity, and establishing conditions for adaptive immune response formation in NALT after infection.
Resident CD8+ Memory T-Cells in NALT: Protection and Tissue Repair After COVID-19
Researchers identified 19 types of immune cells in NALT, including various subsets of CD4+ and CD8+ T-cells, regulatory T-cells, innate lymphoid cells (ILCs), and NK cells.
During acute COVID-19, NALT exhibited an intensified type I and II interferon response, rapidly declining during recovery. However, resident CD8+ memory T-cells (TRM) remained activated and continued producing cytokines, including IL-26 and IFN-γ, essential for protection and tissue repair. These cells rapidly proliferate to enhance immune defense and maintain cytotoxic activity during recovery.
Despite prolonged activation, TRM cells exhibited fewer exhaustion markers than other CD8+ T-cells, highlighting their critical role in protecting, coordinating, and recruiting other T-cell subpopulations and tissue regeneration after viral infection.
B-Cells in NALT: Activation, Class Switching, and Antiviral Response
Researchers identified various B-cell subtypes in NALT, including naïve B-cells, memory B-cells, plasma cells (PCs), and germinal center (GC) B-cells involved in antibody production. During COVID-19, B-cell numbers in NALT increased, particularly during recovery. However, mucosa-associated memory B-cells declined.
IgA- and IgG-secreting PCs were concentrated in the submucosal layer, with enhanced IgA transport across the NALT epithelium due to increased PIGR receptor expression. Conversely, IgG transport via the Fc receptor was reduced, indicating a predominantly systemic rather than nasal IgG response.
During COVID-19, IFN pathways were activated in B-cells, and GC cells exhibited high expression of IFN-I-dependent antiviral genes MX1, ISG15, IRF7, and IFITM1/2. These B-cells could autonomously suppress the virus while simultaneously developing immunological memory.
During recovery, IgG+ B-cell clones expanded. Class switching to IgG rather than IgA appeared to be the preferred mucosal response to SARS-CoV-2 infection.
NALT generates early local antiviral antibodies in COVID-19. Participants with COVID-19 exhibited a significant increase in SARS-CoV-2-specific GC B-cells.
The germinal center response was linked to type I interferon levels: excessive IFN-I expression suppressed BCL6, HMGB2, and BACH2 gene activity, likely limiting GC formation in severe COVID-19 cases.
Conclusion
Although pharyngeal tonsils shrink with age, active lymphoid tissue (NALT) remains in the nasopharynx of adults and contributes to immune responses against viral infections, including SARS-CoV-2.
During acute COVID-19, NALT macrophages activate to protect tissues from damage, while CD8+ memory T-cells maintain antiviral defense. IgA transport to the nasal mucosa is enhanced, whereas IgG produced in NALT primarily supports systemic immunity.
For the first time, researchers confirmed that GC formation occurs in the NALT of adults with COVID-19, similar to observations in children’s adenoids. Recovering patients exhibited GC B-cell activity and high type I interferon response gene expression. However, excessive IFN-I may suppress B-cell immunity and limit GC responses in severe COVID-19 cases.
Useful article, necessary information? Share it!
Someone will also find it useful and necessary:
Reference
Temporal profiling of human lymphoid tissues reveals coordinated defense against viral challenge
