Helle Marcel, Sorg Ursula R, Ptok Johannes, Thomas Rachel E, Pracht Katharina, Petzsch Patrick, de Bruin Alain, Jäck Hans-Martin, Köhrer Karl, Degrandi Daniel, Pfeffer Klaus
Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University, Düsseldorf, Germany.
Institute of Virology, Heinrich Heine University, Düsseldorf, Germany.
Infect Immun. 2025 Sep 9:e0040825. doi: 10.1128/iai.00408-25.
Lymphotoxin β receptor (LTβR/TNFRSF3) signaling plays a crucial role in immune defense. Notably, LTβR-deficient (LTβR) mice exhibit severe defects in innate and adaptive immunity against various pathogens and succumb to infection. Here, we investigated the bone marrow (BM) and peritoneal cavity (PerC) compartments of LTβR mice during infection, demonstrating perturbed B-cell and T-cell subpopulations in the absence of LTβR signaling. infection disrupted BM lymphopoiesis, depleting early and mature B cells in WT mice, whereas mature B cells remained present in LTβR BM. LTβR BM also exhibited reduced MHCII monocytes and a plasma cell compartment skewed toward IgM rather than IgA cells. In addition, BM Tcell subsets were altered, exhibiting decreased double-negative (CD4/CD8) and increased CD4 and CD8 T-cell frequencies. Analysis of the BM transcriptome revealed diminished interferon responses but an upregulated TNFα-NF-κB signaling signature in uninfected and infected LTβR mice, potentially compensating for the absence of LTβR signaling. LTβR mice displayed an altered B-1a to B-1b ratio and a predominant presence of neutrophils in the PerC. In summary, we identified novel immunological alterations in the BM and PerC compartments of LTβR mice, which suggest new roles for LTβR signaling in B- and T-cell homeostasis, migration, and pathogen defense.
淋巴毒素β受体（LTβR/TNFRSF3）信号传导在免疫防御中起着关键作用。值得注意的是，缺乏LTβR的（LTβR）小鼠在针对各种病原体的固有免疫和适应性免疫方面表现出严重缺陷，并易死于感染。在此，我们研究了LTβR小鼠在感染期间的骨髓（BM）和腹腔（PerC）区室，发现在缺乏LTβR信号传导的情况下，B细胞和T细胞亚群受到干扰。感染破坏了野生型小鼠的BM淋巴细胞生成，耗尽了早期和成熟B细胞，而成熟B细胞在LTβR骨髓中仍然存在。LTβR骨髓还表现出MHCII单核细胞减少以及浆细胞区室偏向IgM而非IgA细胞。此外，BM T细胞亚群发生改变，双阴性（CD4/CD8）细胞减少，CD4和CD8 T细胞频率增加。对BM转录组的分析显示，未感染和感染的LTβR小鼠中干扰素反应减弱，但TNFα-NF-κB信号特征上调，这可能补偿了LTβR信号传导的缺失。LTβR小鼠在PerC中显示出B-1a与B-1b比例改变以及中性粒细胞占主导地位。总之，我们在LTβR小鼠的BM和PerC区室中发现了新的免疫改变，这表明LTβR信号传导在B细胞和T细胞稳态、迁移以及病原体防御中具有新的作用。
