Deficient TACI expression on B lymphocytes of newborn mice leads to defective Ig secretion in response to BAFF or APRIL
Deficient TACI expression on B lymphocytes of newborn mice leads to defective Ig secretion in response to BAFF or APRIL
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DOI：
10.4049/jimmunol.181.2.976
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发表时间：
2008-07-15
影响因子：
4.4
通讯作者：
Akkoyunlu, Mustafa
中科院分区：
文献类型：
--
作者：
Kanswal, Sunita;Katsenelson, Nora;Akkoyunlu, Mustafa
包囊细菌的荚膜多糖在新生儿中不诱导免疫应答，并且这种不应答的机制尚不清楚。在成人中，跨膜激活剂和钙调节剂和亲细胞蛋白配体相互作用因子（TACI）是TNFR家族成员分子，在针对多糖疫苗的抗体应答中起关键作用。我们研究了TNF家族细胞因子、TNF家族B细胞活化因子（BAFF）和增殖诱导配体（APRIL）及其受体在新生小鼠中的表达和功能，发现与成年小鼠相比，新生小鼠B淋巴细胞上的TACI表达显著降低（p < 0.0001）。更重要的是，TACI配体BAFF或APRIL不能诱导新生儿B淋巴细胞分泌伊加/IgG/IgM。此外，TACI表达似乎在浆细胞发育中很重要。事实上，与成人相比，用BAFF或APRIL刺激新生儿B淋巴细胞不会导致CD 138表达上调。在体外或体内暴露的新生B淋巴细胞的寡脱氧核苷酸（CpG ODN）导致上调TACI表达的新形成的，滤泡，边缘区以及B1 B淋巴细胞群体，并使他们响应BAFF或APRIL介导的CD 138表达和伊加/IgG分泌。最后，用含有（4-羟基-3-硝基苯基）乙酰基-Ficoll的CpG ODN免疫新生BALB/c小鼠而不是TACI敲除小鼠，导致产生针对（4-羟基-3-硝基苯基）乙酰基的IgG Ab。这些研究结果表明，低TACI表达可能是决定新生儿对包囊细菌感染的易感性和多糖疫苗免疫原性受损的关键因素。最后，CpG ODNs可以通过上调TACI来纠正新生儿对多糖疫苗的应答缺陷。
Capsular polysaccharides of encapsulated bacteria do not induce immune response in newborns and the mechanism for this unresponsiveness is not clear. In adults, transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI) is a TNFR family member molecule with a pivotal role in Ab responses against polysaccharide vaccines. We investigated the expression and the functions of the TNF family cytokines, B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), and their receptors in newborn mice and found that TACI expression on B lymphocytes was dramatically reduced (p < 0.0001) in newborns as compared with adults. More importantly, TACI ligands BAFF or APRIL were unable to induce IgA/IgG/IgM secretion from newborn B lymphocytes. Additionally, TACI expression seems to be important in plasma cell development. Indeed, in contrast to adults, stimulation of newborn B lymphocytes with BAFF or APRIL did not result in up-regulation of CD138 expression. In vitro or in vivo exposure of newborn B lymphocytes to oligodeoxynucleotides (CpG ODN) led to up-regulation of TACI expression on newly formed, follicular, and marginal zone as well as B1 B lymphocyte populations, and rendered them responsive to BAFF- or APRIL-mediated CD138 expression and IgA/IgG secretion. Finally, immunization of newborn BALB/c mice but not TACI knockout mice with CpG ODN containing (4-hydroxy-3-nitrophenyl)acetyl-Ficoll led to development of IgG Abs against (4-hydroxy-3-nitrophenyl)acetyl. These findings demonstrate that low TACI expression may be a critical factor that determines the susceptibility of newborns to infections with encapsulated bacteria and the impaired immunogenicity of polysaccharide vaccines. Finally, CpG ODNs may correct deficient newborn response to polysaccharide vaccines by up-regulating TACI.