How lymphoid tissues protect against viral infections

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Feb 7 2025

A recent Nature Immunology study explores the cellular and molecular adaptations associated with human secondary lymphoid tissue in adults during viral infection.

Study: Temporal Profiling of Human Lymphoid Tissues Reveals Coordinated Defense against Viral Challenge. Image Credit: sokolova_sc / Shutterstock.com

Lymphoid organs and immune protection

Lymphoid tissues play a vital role in adaptive immunity. Secondary lymphoid organs are involved in the spatial and temporal arrangement of immune cells, which facilitates cellular interactions and the timely production of pathogen-specific responses.

T and B lymphocytes are distributed in distinct regions of lymphoid tissues; however, these cells are not present within germinal centers (GCs). In general, GC B-cells obtain antigens from follicular dendritic cells (FDCs) and subsequently present these molecules to PD⁺CD4⁺ T follicular helper (T_FH) cells. This interaction leads to the generation of memory B-cells and antibody-secreting plasmablasts, which confer protection against current and future infection.

Several animal models have been established to elucidate how subcapsular sinus macrophages prevent the spread of lymph-borne viruses and bacteria. Nevertheless, it remains unclear how lymphoid tissues respond during these infections in humans.

The pharyngeal tonsils, which are otherwise known as adenoids, are major sites of nasal-associated lymphoid tissue (NALT). The epithelial layer of adenoids consists of antigen-transporting M-cells that transport antigens from the surface of the tonsils to underlying B-cell follicles and T-cell-containing interfollicular areas.  This structural feature leads to the generation of protective antibody-secreting and memory cells following nasal challenge.

Few studies have examined the role of adenoids in adolescence or how NALTs contribute to local mucosal adaptive immune responses in adult humans. This research is crucial to understanding whether macrophage heterogeneity influences immune defences associated with lymphoid tissue in humans.

About the study

The current study explored NALT activity during a local infection, particularly by maintaining the cells and infrastructure required to support an ongoing adaptive immune response.

Multi-parameter flow cytometry, single-cell ribonucleic acid (RNA) sequencing (scRNA-seq), and confocal imaging on adult NALT biopsies were performed to investigate the cellular and molecular adaptations associated with human secondary lymphoid tissue in adults experiencing a viral infection. Nasal samples were collected under direct endoscopic visualization.

Both patients diagnosed with coronaviruse disease 2019 (COVID-19) and healthy controls were recruited from Cambridge in the United Kingdom between May 2020 and July 2021, as well as between August 2019 and November 2019, respectively.

All study participants were 18 years of age or older. Individuals with a history of chronic infection or malignancy were excluded from the analysis.

Study findings

The study cohort comprised 23 individuals, 10 of whom were healthy controls, eight experienced acute COVID-19, and five were SARS-CoV-2 convalescent patients. Post-nasal space biopsies and blood samples were collected from all study participants.

Data on 162,738 cells were generated followed by the identification of 20 major cell clusters across nasal tissues and peripheral blood mononuclear cells (PBMCs). In addition to the presence of stromal cells, epithelial cells, and a wide range of immune cell populations, a significant overrepresentation of GC B-cells and T_FH cells was observed in nasal samples. GC B-cells were abundantly present in convalescent NALT samples.

Confocal imaging of NALT biopsies led to the identification of B-cell follicles containing CD21-expressing FDCs and spatially distinct T-cell-rich areas. COVID-19 samples exhibited a higher number of differentially expressed genes (DEGs) as compared to controls.

Mononuclear phagocytes (MNPs), such as conventional dendritic cells (cDCs), plasmacytoid dendritic cells (pDCs), basophils, and macrophages, contribute to lymphoid tissue defense and repair. The study findings suggest that calprotectin-producing monocytes and neutrophil extracellular trap (NET)-losing neutrophils collectively defend underlying lymphoid tissues after epithelial cell damage by viral infection.

A functional switch was observed in monocyte-derived DCs in acute COVID-19 away from antigen presentation and toward neutrophil recruitment. Furthermore, a robust induction of interferon (IFN)-induced antiviral programs occurred in NALT T-cells in active COVID-19 infection that quickly declined in convalescence.

However, CD8 T_RM cells alone exhibited clonal expansion and evidence of ongoing cytotoxic activity in convalescent individuals, along with the production of antimicrobial peptides, IFNγ, and pro-repair molecules.

As compared to other subsets of CD8 T-cells, T_RM cells exhibited reduced transcriptional evidence of exhaustion. Experimental findings indicated that type 1 IFN may inhibit the progression of the GC reaction, which could explain the limited GC formation observed during severe COVID-19.

Conclusions

The study findings provide novel insights into the processes involved in nasal adaptive immune responses generated during viral infection. The NALT sampling method could be used in the future to analyze longitudinal changes in lymphoid organs in humans during disease and after treatment.