Bcl6 expression is associated with a distinct immune landscape and spatial transcriptome in COVID-19
Cloé Brenna, … , Raphael Gottardo, Constantinos Petrovas
Cloé Brenna, … , Raphael Gottardo, Constantinos Petrovas
Published September 9, 2025
Citation Information: JCI Insight. 2025;10(20):e189134. https://doi.org/10.1172/jci.insight.189134.
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Research Article Immunology Infectious disease

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

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.

Authors

Cloé Brenna, Bernat Bramon Mora, Kalliopi Ioannidou, Julien Bodelet, Mia L. Siebmanns, Simon Burgermeister, Spiros Georgakis, Michail Orfanakis, Yannick D. Muller, Nazanin Sédille, Matthew J. Feinstein, Jon W. Lomasney, Oliver Y. Chén, Giuseppe Pantaleo, Sabina Berezowska, Laurence de Leval, Raphael Gottardo, Constantinos Petrovas

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Figure 3

Increasing Bcl6 expression is associated with altered spatial distribution of RF immune cell subsets.

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Increasing Bcl6 expression is associated with altered spatial distributi...
(A) Correlation between PD1hiCD57hi Tfh cells and CD20hi/dimKi67hiBcl6hi B cells across follicles in LD-LNs. Left panel: RF-Bcl6int donors (pink). Right panel: RF-Bcl6hi donors (green). R² and P values are reported. (B) Ratio of CD20hi/dimKi67hiBcl6hi B cells to PD1hiCD57hi Tfh cells in RF-Bcl6int (pink) versus RF-Bcl6hi (green) donors. (C) Net area under the G-function curve (AUCabove – AUCbelow) by distance (r, μm), comparing spatial organization of GC B cells and Tfh cells subsets across groups (tissues from CHUV were analyzed). (D) Left panel: Connectivity plot from Donor 17-Follicle 6 (RF-Bcl6hi) showing spatial links from the most central GC B cell (yellow) to Tfh cells (green). Right panel: Histogram of minimum Euclidean distances from Donor 17-Follicle 6 (RF-Bcl6hi). (E) Dot plot of mean minimum Euclidean distances between CD20hi/dimKi67hi B cells and PD1hiCD57hi Tfh cells in HLN-Controls (blue), RF-Bcl6int (pink), and RF-Bcl6hi (green). Each point represents one follicle. Mann-Whitney U; *P ≤ 0.05, **P ≤ 0.01, ****P ≤ 0.0001. Raw P-values are shown on the graph, and both raw and FDR-adjusted P-values are reported in Supplemental Table 11.