Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Department of Medicine, University of California, San Francisco, CA, USA.
Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA.
Nat Immunol. 2023 Oct;24(10):1762-1777. doi: 10.1038/s41590-023-01597-9. Epub 2023 Aug 31.
Multivalent viral epitopes induce rapid, robust and T cell-independent humoral immune responses, but the biochemical basis for such potency remains incompletely understood. We take advantage of a set of liposomes of viral size engineered to display affinity mutants of the model antigen (Ag) hen egg lysozyme. Particulate Ag induces potent 'all-or-none' B cell responses that are density dependent but affinity independent. Unlike soluble Ag, particulate Ag induces signal amplification downstream of the B cell receptor by selectively evading LYN-dependent inhibitory pathways and maximally activates NF-κB in a manner that mimics T cell help. Such signaling induces MYC expression and enables even low doses of particulate Ag to trigger robust B cell proliferation in vivo in the absence of adjuvant. We uncover a molecular basis for highly sensitive B cell responses to viral Ag display that is independent of encapsulated nucleic acids and is not merely accounted for by avidity and B cell receptor cross-linking.
多价病毒表位可诱导快速、强劲且无需 T 细胞参与的体液免疫应答，但这种强效性的生化基础仍不完全清楚。我们利用一组工程化的病毒大小的脂质体来展示模型抗原（Ag）鸡卵溶菌酶的亲和力突变体。颗粒状 Ag 会诱导出强烈的“全有或全无”B 细胞反应，这种反应依赖于密度而不依赖于亲和力。与可溶性 Ag 不同，颗粒状 Ag 通过选择性逃避 LYN 依赖性抑制途径，在最大程度上激活 NF-κB，从而模拟 T 细胞辅助，从而在 B 细胞受体下游诱导信号放大。这种信号诱导 MYC 表达，使得即使是低剂量的颗粒状 Ag 也能在没有佐剂的情况下在体内引发强烈的 B 细胞增殖。我们揭示了一种对病毒 Ag 展示具有高度敏感性的 B 细胞反应的分子基础，这种反应不依赖于包裹的核酸，并且不仅仅可以用亲和力和 B 细胞受体交联来解释。
