Work

iHALT unlocks liver functionality as a surrogate secondary lymphoid organ

Year: 2025

Type: article

Abstract: Upon viral infection, the current paradigm of humoral immunity posits that germinal centre reactions occurring within secondary lymphoid organs (SLOs) yield effector plasma cells that subsequently traffic to infected organs or the bone marrow1–3. However, it is not well understood how viral tissue tropism may govern the spatiotemporal dynamics of such responses. Here we demonstrate that infection with a prototypical systemic virus indeed induces liver-trafficking plasma cells generated in SLOs, whereas strictly hepatotropic hepaciviral infection elicits locally primed, virus-specific plasma cells in the liver independently of SLO contribution. Such locally derived progenies emerged from inducible hepatic-associated lymphoid tissue (iHALT) structures containing generative foci of T follicular helper cells, myeloid cells and germinal centre-like B cells, often arising from single founder clones unique to individual periportal structures and locally supporting somatic hypermutation. Critically, the cellular composition, cell–cell contact partners and microarchitecture of such iHALT structures in mice were closely mirrored upon hepaciviral infection in humans. Functionally dependent upon CD40L signalling and cognate B cell receptor specificity, emerging CXCR4+VLA-4+LFA-1+CD44+CD138+ plasma cells were immediately retained along CXCL12+fibronectin+ICAM2+osteopontin+type I collagen+ periportal fibroblast tracts, acting as cognate anchoring pairs that were critical to their maintenance therein. In summary, we characterize humoral immunity exclusively generated and maintained within its extralymphoid site of viral infection in the liver amidst SLO dormancy, in which functional iHALT successfully compensates for strictly hepatotropic virus-induced SLO-evasion strategies to prevent persistent infection. Liver-restricted viral infection in mice results in secondary lymphoid organ dormancy and the compensatory induction of specialized lymphoid tissue in the liver, the structural features and functional outputs of which are closely mirrored in humans.

Source: Nature

DOI: 10.1038/s41586-025-09803-4