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

## TL;DR

This study shows how immune follicles in lung lymph nodes change during severe COVID-19, revealing new pathways involved in antibody production.

## Contribution

The study identifies distinct immune landscapes and molecular pathways linked to Bcl6 expression in lung-draining lymph nodes during acute COVID-19.

## Key findings

- Three donor groups were identified based on Bcl6 prevalence in reactive follicles.
- RF-Bcl6hi lymph nodes showed increased B/Tfh cell subsets and GC-promoting gene activity.
- TH1-associated pathways were upregulated in RF-Bcl6no/lo tissues, contrasting with RF-Bcl6hi tissues.

## Abstract

The regulation of follicular (F) and germinal center (GC) immune reactivity in human lymph nodes (LNs), particularly during the acute stages of viral infection, remains poorly understood. We have analyzed lung-draining lymph nodes (LD-LNs) from COVID-19 autopsies using multiplex imaging and spatial transcriptomics to examine the immune landscape with respect to follicular immune reactivity. We identified 3 groups of donors based on the Bcl6 prevalence of their reactive follicles (RFs): RF-Bcl6no/lo, RF-Bcl6int, and RF-Bcl6hi. A distinct B/Tfh immune landscape, associated with increased prevalence of proliferating B cell and Tfh cell subsets, was found in RF-Bcl6hi LD-LNs. The comparison between LD-LNs and subdiaphragmatic (SD) LNs from the same donor revealed a divergent Bcl6 expression between the 2 anatomical sites. LD-LN Bcl6 expression was also associated with a distinct spatial transcriptomic profile. TH1-associated genes/pathways (e.g., CXCR3, STAT5, TNF signaling) were significantly upregulated in RF-Bcl6no/lo tissues, while the RF-Bcl6hi tissues exhibited significant upregulation of GC-promoting genes/pathways (e.g., CXCL13, B-cell receptor signaling). Our findings reveal a heterogeneous F/GC landscape in COVID-19 LD-LNs, highlighting specific molecular targets and pathways that could regulate human F/GC immune dynamics during acute viral infections.

We reveal how COVID-19 reshapes immune follicles in lung lymph nodes, identifying distinct molecular pathways that control antibody responses during acute viral infection.