Selective clonal attrition of high-affinity B cells in chronic viral infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE296780 | GEO | 2026/03/17
REPOSITORIES: GEO
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Project description:Affinity maturation and vaccine efficacy are compromised during chronic viral infections, yet the underlying mechanisms remain unclear. Using the LCMV Cl13 model, we show that IFN-I signaling in B cells plays a central role. IFN-I promotes early B cell activation but reduces clonal diversity and delays IgG1⁺ B cell entry into germinal centers, impairing high-affinity clone selection. Deletion of IFNAR1 in B cells partially restores NP-specific IGHV1-72 usage and GC access but fails to fully rescue affinity maturation, suggesting a contribution of extrinsic factors. Somatic hypermutation remains elevated in both genotypes, though slightly reduced in IFNAR1⁻/⁻ B cells. BASELINe analysis indicates weaker selection pressure in CDRs, potentially reflecting impaired affinity-based selection. This defect correlates with a reduced TFR/TFH ratio. Our results show that intrinsic and extrinsic IFN-I-dependent mechanisms synergize to disrupt B cell fate. These findings establish IFN-I as a key regulator of humoral immunity and highlight mechanisms underlying poor vaccine response.
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Project description:Affinity maturation and vaccine efficacy are compromised during chronic viral infections, yet the underlying mechanisms remain unclear. Using the LCMV Cl13 model, we show that IFN-I signaling in B cells plays a central role. IFN-I promotes early B cell activation but reduces clonal diversity and delays IgG1⁺ B cell entry into germinal centers, impairing high-affinity clone selection. Deletion of IFNAR1 in B cells partially restores NP-specific IGHV1-72 usage and GC access but fails to fully rescue affinity maturation, suggesting a contribution of extrinsic factors. Somatic hypermutation remains elevated in both genotypes, though slightly reduced in IFNAR1⁻/⁻ B cells. BASELINe analysis indicates weaker selection pressure in CDRs, potentially reflecting impaired affinity-based selection. This defect correlates with a reduced TFR/TFH ratio. Our results show that intrinsic and extrinsic IFN-I-dependent mechanisms synergize to disrupt B cell fate. These findings establish IFN-I as a key regulator of humoral immunity and highlight mechanisms underlying poor vaccine response.
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Project description:T cells activated by chronic antigen exposure in the setting of viral infections or cancer can adopt an exhausted T cell (TEx) state, characterized by reduced effector function and proliferative capacity, and the upregulation of inhibitory receptors. Here, we generate a single-cell multi-omic atlas of T cell exhaustion in chronic viral infection that redefines the phenotypic diversity and molecular regulation of TEx states. Longitudinal analysis of the T cell response identifies an early effector phenotype that is epigenetically primed for TEx differentiation. However, clonal T cell trajectories defined using paired single-cell RNA and T cell receptor (scRNA/TCR-seq) sequencing reveal divergent differentiation trajectories among clones that recognize shared antigens, resulting in TEx- or effector memory-biased clone behaviors. Multi-organ clonal analysis reveals that T cell clone behaviors are sensitive to the tissue environment, and the liver niche preclude the development of effector memory phenotypes and induce exaggerated exhaustion. Finally, we show that divergent clonal trajectories are driven by differences in TCR affinity, and that high-affinity T cell clones preferentially adopt the divergent fate, while low-affinity clones adopt effector memory fates that are deleted in high antigen niches. These findings reveal heterogeneity in clonal T cell responses to chronic antigen and link TCR signal strength and epigenetic programming to TEx cell fates and persistence, which may be manipulated for cancer immunotherapy.
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