Fazilleau, N. | Search bioRxiv

bioRxiv2025

Access to germinal center IL-4 microniches drives tissue-divergence of IgE memoryresponses

Immunoglobulin E (IgE) drives allergic disease, yet how memory B cells (MBCs) reactivate to produce IgE, and how tissue localization shapes recall responses, remains unclear. Using mouse models of airborne exposure to house dust mites and Alternaria, we found that allergen sensitization generates lymphoid- and lung-resident MBCs. Upon allergen re-exposure, these populations followed distinct differentiation trajectories: lymph node MBCs engaged a germinal center (GC)-dependent pathway that generated both IgG1 and IgE plasma cells (PCs), whereas lung MBCs followed a GC-independent route producing mainly IgG1 PCs. GC re-entry granted MBCs access to an IL-4-rich microniche formed by Tfh cells, which was essential for IgE production. Disrupting GC re-entry, IL-4 signaling, or Tfh-derived IL-4 during recall markedly reduced allergen-specific IgE titers. These findings reveal a spatially and cytokine-restricted mechanism that confines IgE memory to lymphoid organs, positioning GC IL-4 microniches as anatomical safeguards against IgE production at barrier sites frequently exposed to environmental antigens.

immunology↗

bioRxiv2022

A selective LIS1 requirement for mitotic spindle assembly discriminates distinct T-cell division mechanisms within the T-cell lineage

The ability to proliferate is a common feature of most T-cell populations. However, proliferation follows different cell-cycle dynamics and is coupled to different functional outcomes according to T-cell subsets. Whether the mitotic machineries supporting these qualitatively distinct proliferative responses are identical remains unknown. Here, we show that disruption of the microtubule-associated protein LIS1 leads to proliferative defects associated with a blockade of T-cell development after {beta}-selection and of peripheral CD4+ T cell expansion after antigen priming. In contrast, cell divisions in CD8+ T cells occurred independently of LIS1 following T-cell antigen receptor stimulation, although LIS1 was required for proliferation elicited by pharmacological activation. In thymocytes and CD4+ T cells, LIS1-deficiency did not affect signaling events leading to activation but led to an interruption of proliferation after the initial round of division and to p53-induced cell death. Proliferative defects resulted from a mitotic failure, characterized by the presence of extra-centrosomes and the formation of multipolar spindles, causing abnormal chromosomes congression during metaphase and separation during telophase. LIS1 was required to stabilize dynein/dynactin complexes, which promote chromosome attachment to mitotic spindles and ensure centrosome integrity. Together, these results suggest that proliferative responses are supported by distinct mitotic machineries across T-cell subsets.

immunology↗