Bcl6 expression is associated with a distinct immune landscape and spatial transcriptome in COVID-19

Area of Science:

• Immunology
• Virology
• Pathology

Background:

• Follicular (F) and germinal center (GC) immune regulation in human lymph nodes (LNs) during acute viral infections is not well understood.
• Understanding these dynamics is crucial for developing effective antiviral therapies.

Purpose of the Study:

• To investigate the immune landscape of lung-draining lymph nodes (LD-LNs) in COVID-19 autopsies.
• To characterize follicular immune reactivity and its association with viral infection stages.

Main Methods:

• Analysis of LD-LNs from COVID-19 autopsies using multiplex imaging and spatial transcriptomics.
• Classification of reactive follicles (RFs) into three groups based on Bcl6 expression (RF-Bcl6no/lo, RF-Bcl6int, RF-Bcl6hi).
• Comparison of Bcl6 expression and spatial transcriptomic profiles between LD-LNs and subdiaphragmatic (SD) LNs.

Main Results:

• Three distinct follicular immune landscapes (RF-Bcl6no/lo, RF-Bcl6int, RF-Bcl6hi) were identified in LD-LNs.
• RF-Bcl6hi LD-LNs showed a unique B/Tfh cell landscape with increased proliferation.
• Divergent Bcl6 expression was observed between LD-LNs and SD-LNs, with distinct transcriptomic profiles associated with Bcl6 levels and TH1/GC pathways.

Conclusions:

• COVID-19 induces a heterogeneous follicular and germinal center landscape in lung-draining lymph nodes.
• Specific molecular targets and pathways regulating F/GC immune dynamics during acute viral infections were highlighted.
• Findings provide insights into human immune responses during acute viral infections, particularly in the context of COVID-19.