Induction of polysaccharide vaccine responses in the young by interleukin-7

对经典T细胞非依赖性（TI）抗原（如细菌荚膜多糖）的抗体应答 具有高度保护性，在控制许多临床上重要的感染中发挥关键作用。为 原因仍然知之甚少，幼儿不能对TI抗原产生抗体应答， 结果是更容易遭受危及生命的感染，特别是来自包囊的感染。 细菌病原体与年幼的儿童一样，年幼的小鼠对多糖抗原的反应很差，而 成年人以及成年小鼠可以对多糖抗原产生非常有效的应答。B1b 淋巴细胞是成熟B细胞的一个亚群，其数量响应于多种TI抗原而增加 包括肺炎链球菌的3型多糖（PPS 3），阴沟肠杆菌的葡聚糖， 伤寒沙门氏菌Vi多糖和赫氏疏螺旋体表面抗原H因子结合蛋白A。 此外，这些细胞产生快速的初级抗体以及持久的记忆B细胞应答。 尽管有B1b细胞，年轻的小鼠对多糖抗原的反应受损，这表明， 年轻人的B细胞与成年人的不同。由于生命早期的B淋巴细胞生成主要是IL-7- 虽然在成人中是IL-7依赖性的，但我们假设B细胞在IL-7存在下发育 是产生抗多糖抗体应答所必需的。为了支持这一点，我们发现，尽管 具有B1b细胞的年轻野生型、成年IL-7-/-或成年IL-7R-/-小鼠在应答 经典的TI抗原如4-羟基-3-硝基苯基-乙酰基-Ficoll（NP-Ficoll）、细菌葡聚糖和PPS 疫苗，并且不能存活S. PPS免疫后的肺炎攻毒。此外，我们发现， IL-7的转基因表达促进了年轻人的抗PPS应答，并赋予了对S. 肺炎。这些数据支持IL-7依赖性B细胞在产生TI中起关键作用的假设 体液免疫为了将这些发现转化为人类婴儿，我们使用了新生儿NOD/SCID/cnull 移植人脐带血CD34+造血干细胞的小鼠， 系统"小鼠（HIS小鼠）模型。我们已经发现这些HIS小鼠产生了几个B细胞亚群 包括B1细胞，并且它们中的大多数表现出不成熟的B细胞表型。此外，正如年轻的 在儿童中，HIS小鼠对PPS反应较差，对B反应次优。赫姆斯。由于IL-7主要由 非造血基质细胞，鼠IL-7是人淋巴细胞发育的不良刺激物， 这种损伤可能是由于HIS小鼠中缺乏人IL-7驱动的B细胞。为了支持这一点，我们发现， 用人IL-7补充HIS小鼠显著增加了对B的体液应答。赫姆斯。的 该提案中概述的目标寻求：1）确定IL-7是否增加多糖的数量， 特异性B1b细胞;和2）确定在IL-7存在或不存在下产生的B1b细胞是否 质的不同。

Antibody responses to classical T cell-independent (TI) antigens such as bacterial capsular polysaccharides are highly protective, and play a critical role in controlling a number of clinically important infections. For reasons that remain poorly understood young children cannot mount antibody responses to TI antigens and as a consequence are much more prone to suffer from life-threatening infections, particularly from encapsulated bacterial pathogens. As with young children, young mice respond poorly to polysaccharide antigens, while human adults as well as adult mice can mount a very efficient response to polysaccharide antigens. B1b lymphocytes are a subset of mature B cells that increases in number in response to a variety of TI antigens including type 3 polysaccharide of Streptococcus pneumoniae (PPS3), ¿1,3 dextran of Enterobacter cloacae, Vi polysaccharide of Salmonella typhi and Factor H binding protein A, a surface antigen of Borrelia hermsii. Furthermore, these cells generate rapid primary antibody as well as long-lasting memory B cell responses. Despite having B1b cells, young mice are impaired in responding to polysaccharide antigens, suggesting that B cells in the young are distinct from those in adults. Since B lymphopoeisis early in life is largely IL-7- independent, while in adults it is IL-7-dependent, we hypothesize that B cells developed in the presence of IL-7 are required for generating anti-polysaccharide antibody responses. In support of this, we found that despite having B1b cells, young wildtype, adult IL-7-/- or adult IL-7R¿-/- mice are severely impaired in responding to classical TI antigens such as 4-hydroxy-3-nitrophenyl-acetyl-Ficoll (NP-Ficoll), bacterial dextran and PPS vaccine, and do not survive S. pneumoniae challenge after PPS immunization. Furthermore, we found that transgenic expression of IL-7 promotes the anti-PPS response in young and confers protective immunity to S. pneumoniae. These data support the hypothesis that IL-7-dependent B cells play a crucial role in generating TI humoral immunity. To translate these findings to human infants we have utilized neonatal NOD/SCID/¿cnull mice engrafted with human umbilical cord blood CD34+ hematopoietic stem cells to create a "Human Immune System" mouse (HISmouse) model. We have found that these HISmice generate several subsets of B cells including B1 cells and the majority of them exhibit an immature B cell phenotype. Moreover, just as young children, HISmice responded poorly to PPS and sub-optimally to B. hermsii. Since IL-7 is produced mainly by non-hematopoietic stromal cells, and murine IL-7 is poor stimulator of human lymphocyte development, this impairment could be due to the lack of human IL-7-driven B cells in HISmice. In support of this we found that supplementation of HISmice with human IL-7 dramatically increases humoral responses to B. hermsii. The aims outlined in this proposal seek to: 1) determine whether IL-7 increases the number of polysaccharide- specific B1b cells; and 2) determine whether the B1b cells generated in the presence or absence of IL-7 are qualitatively different.