Spatial compartmentalization shapes distinct germinal center states during respiratory viral infection

Germinal centers (GCs) typically arise within the lymph node cortex, where follicular dendritic cell (FDC) networks and follicular helper T cells coordinate B-cell expansion, affinity maturation, and durable immunity. Whether proliferating B-cell aggregates in the medulla engage bona fide GC programs or instead represent a distinct GC-like differentiation state remains unresolved.

In this study, using mediastinal lymph nodes from SARS-CoV-2-infected cynomolgus macaques, we combined immunofluorescence with Xenium spatial transcriptomics to identify LYVE1+ sinus-associated medullary GC structures (mGCs) alongside conventional cortical GCs (cGCs).

mGCs shared core GC-associated modules with cGCs but showed niche-divergent features, including increased expression of PRDM1, MZB1, and VWF and decreased expression of IRF8, CD27, and CD86. mGCs retained organized follicular architecture but showed lower CD4+ T and GC B cell densities, greater plasma cell representation, and enrichment of pDCs, NK cells, and stromal populations. Compared with cGCs, mGCs lacked polarized CD35+ FDC and CD3+ T cell network topology, exhibited reduced CXCL12 availability, and showed a higher IgM/IgG ratio. During early reinfection, medullary secondary follicles contracted sharply and were associated with higher Foxp3+ cell density.

These findings support a model in which lymph node microanatomy imprints a distinct mGC state, diversifying humoral immune architecture during respiratory viral infection.