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Spatiotemporal dynamics of the lymph adaptive immune repertoire in response to viral infection

ABSTRACT: The spatial organization of adaptive immune cells within lymph nodes is critical for understanding immune responses during infection and disease. Here, we investigated the spatial and temporal changes in the adaptive immune repertoire (AIR) in the draining lymph node after footpad infection with Vaccinia virus (VACV) in mice. To achieve this, we integrated high-resolution spatial transcriptomics with high-fidelity long-read adaptive immune receptor sequencing of T and B cell receptors. This approach enables simultaneous analysis of whole transcriptomes and AIR in their spatial context. We mapped the spatial distribution and temporal dynamics of immune phenotypes and AIRs at 3, 7, 10, 14, and 21 days post-infection. Our analysis revealed heterogeneous activation niches characterized by Interferon-gamma (IFN-γ) during the early stages of infection. We observed sub-anatomical structures within the germinal center (GC) and provided direct evidence that antibody-producing plasma cells differentiate and exit the GC from the dark zone. Furthermore, we traced the spatial lineage trajectory of B cell clones and found evidence of B cell maturation across multiple GCs. Overall, this method offers valuable insights into the spatial dynamics of immune responses within lymphoid organs, with relevance for spatiotemporal studies of the immune system response to an infectious agent.

ORGANISM(S): Mus musculus

PROVIDER: GSE286452 | GEO | 2025/03/11

REPOSITORIES: GEO

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Project description:The germinal center response or reaction (GCR) is a hallmark event of adaptive humoral immunity. Unfolding in the B cell follicles of the secondary lymph organs, a GC culminates in the production of high-affinity antibody-secreting plasma cells along with memory B cells. By interacting with follicular dendritic cells (FDC) and T follicular helper (Tfh) cells, GC B cells exhibit complex spatiotemporal dynamics. Driving the B cell dynamics are the intracellular signal transduction and gene regulatory network that responds to cell surface signaling molecules, cytokines, and chemokines. As our knowledge of the GC continues to expand in depth and in scope, mathematical modeling has become an important tool to help disentangle the intricacy of the GCR and inform novel mechanistic and clinical insights. While the GC has been modeled at different granularities, a multiscale spatial simulation framework – integrating molecular, cellular, and tissue-level responses – is still rare. Here, we report our recent progress toward this end with a hybrid stochastic GC framework developed on the Cellular Potts Model-based CompuCell3D platform. Tellurium is used to simulate the B cell intracellular molecular network comprising NF-κB, FOXO1, MYC, AP4, CXCR4, and BLIMP1 that responds to B cell receptor (BCR) and CD40-mediated signaling. The molecular outputs of the network drive the spatiotemporal behaviors of B cells, including cyclic migration between the dark zone (DZ) and light zone (LZ) via chemotaxis; clonal proliferative bursts, somatic hypermutation, and DNA damage-induced apoptosis in the DZ; and positive selection, apoptosis via a death timer, and emergence of plasma cells in the LZ. Our simulations are able to recapitulate key molecular, cellular, and morphological GC events including B cell population growth, affinity maturation, and clonal dominance. This novel modeling framework provides an open-source, customizable, and multiscale virtual GC simulation platform that enables qualitative and quantitative in silico investigations of a range of mechanic and applied research questions on the adaptive humoral immune response in future.

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Spatiotemporal dynamics of the lymph adaptive immune repertoire in response to viral infection

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