Perforin-2 (P2) is a pore-forming protein with cytotoxic activity against intracellular bacterial pathogens. P2 knockout (P2KO) mice are unable to control infections and die from normally non-lethal bacterial infections. Here we show that P2KO mice as compared to WT mice show significantly higher levels of systemic inflammation, measured by inflammatory markers in serum, due to continuous microbial translocation from the gut which cannot be controlled as these mice lack P2. Systemic inflammation in young and old P2KO mice induces intrinsic B cell inflammation. Systemic and B cell intrinsic inflammation are negatively associated with in vivo and in vitro antibody responses. Chronic inflammation leads to class switch recombination defects, which are at least in part responsible for the reduced in vivo and in vitro antibody responses in young and old P2KO vs. WT mice. These defects include the reduced expression of activation-induced cytidine deaminase (AID), the enzyme for class switch recombination, somatic hypermutation and IgG production and of its transcriptional activators E47 and Pax5. Of note, the response of young P2KO mice is not different from the one observed in old WT mice, suggesting that the chronic inflammatory status of mice lacking P2 may accelerate, or be equivalent, to that seen in old mice. The inflammatory status of the splenic B cells is associated with increased frequencies and numbers of the pro-inflammatory B cell subset called Age-associated B Cells (ABCs) in the spleen and the visceral adipose tissue (VAT) of P2KO old mice. We show that B cells differentiate into ABCs in the VAT following interaction with the adipocytes and their products, and this occurs more in the VAT of P2KO mice as compared to WT controls. This is to our knowledge the first study on B cell function and antibody responses in mice lacking P2.

Perforin-2（P2）是一种成孔蛋白，对细胞内细菌病原体具有细胞毒活性。P2基因敲除（P2KO）小鼠无法控制感染，并因正常的非致命细菌感染而死亡。在这里，我们显示，与WT小鼠相比，P2KO小鼠表现出明显更高的全身炎症水平，这是通过血清中的炎性标记物来衡量的，这是由于无法持续控制肠道中微生物的连续移位，因为这些小鼠缺乏P2。幼小和成年P2KO小鼠的全身性炎症均可诱发内在的B细胞炎症。全身性和B细胞内在炎症与负相关体内 和 体外抗体反应。慢性炎症导致类别转换重组缺陷，这至少部分是导致炎症减少的原因体内 和 体外幼小和老年P2KO与WT小鼠的抗体反应。这些缺陷包括激活诱导的胞苷脱氨酶（AID），用于类别转换重组，体细胞超突变和IgG产生的酶及其转录激活因子E47和Pax5的表达降低。值得注意的是，年轻的P2KO小鼠的反应与在老WT小鼠中观察到的反应没有什么不同，这表明缺乏P2的小鼠的慢性炎症状态可能会加速或与老小鼠相同。脾脏B细胞的炎症状态与P2KO老小鼠的脾脏和内脏脂肪组织（VAT）中称为年龄相关B细胞（ABC）的促炎症B细胞亚群的频率和数量增加有关。我们显示B细胞在与脂肪细胞及其产物相互作用后在VAT中分化为ABCs，与WT对照相比，它在P2KO小鼠的VAT中发生的更多。据我们所知，这是缺乏P2小鼠中B细胞功能和抗体反应的第一项研究。