Lymphatic regulation of germinal center dynamics

Host

Carlos Minutti, PhD, Immunoregulation Lab

Venue

Seminar Room

Abstract

Germinal center (GC) responses generate high-affinity antibodies through iterative cycles of B cell proliferation and affinity-based selection, yet the tissue-level mechanisms that regulate GC fitness remain poorly understood. We have demonstrated that lymphatic remodeling is a critical determinant of productive humoral immunity following viral infection. Using lymphatic endothelial cell-specific inhibition of VEGFR2- dependent lymphangiogenesis, we found that impaired lymphatic remodeling paradoxically produces enlarged but dysfunctional GCs that fail to generate optimal virus-specific class-switched antibody responses and protective immunity. Despite preserved GC architecture, enlarged GCs exhibit defective clonal selection, reduced proliferative bursts, and impaired affinity maturation. Mathematical modeling and functional studies revealed that these defects arose from fewer productive interactions between B cells and T follicular helper cells in oversized GCs, uncovering an evolutionarily conserved optimal GC size across mammalian species. Mechanistically, viral dissemination to draining lymph nodes induces interferon-dependent suppression of perifollicular lymphangiogenesis, promoting excessive follicular expansion and reducing selection efficiency. Conversely, protecting lymphatic endothelial cells from virus-induced interferon signaling restores lymphatic growth, constrains follicle size, and rescues GC function. Together, these findings establish lymphatic vessels as active regulators of GC architecture and function rather than passive conduits for antigen transport. By spatially compartmentalizing antigen and inflammatory signals, lymphatic remodeling optimizes GC size, affinity-based selection, and the generation of protective antibodies. These findings identify lymphatic remodeling as a fundamental regulator of humoral immunity and suggest that therapeutic modulation of lymphatic responses may improve vaccine efficacy and protective antibody generation.

Bio

Carla Nowosad is a British immunologist and Assistant Professor in the Department of Pathology at New York University Grossman School of Medicine. Her research explores the spatial regulation of germinal center B cell responses across different tissues. She lives in Manhattan with her husband and daughter, where they enjoy eating their way around the city's many delicious bakeries.

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Champalimaud Research (CR) Colloquia Series is a seminar programme organised by the Champalimaud Centre for the Unknown to promote the discussion about the most interesting and significant questions in neuroscience and physiology & cancer with appointed speakers by the CR Community.