Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Eur J Immunol. 2013 Nov;43(11):2980-92. doi: 10.1002/eji.201243068. Epub 2013 Aug 12.
Fc receptor-like (FCRL) molecules are preferentially expressed by B lymphocytes and possess tyrosine-based immunoregulatory function. Although they generally inhibit B-cell receptor signaling, their influence on other activation pathways remains largely unexplored. In humans, FCRL3 encodes a type I transmembrane protein harboring both cytoplasmic ITAM and ITIM elements that can repress B-cell receptor activation. Despite this inhibitory property, mounting associations for FCRL3 with autoimmune and lympho-proliferative disorders imply a role for it in promoting B-cell pathogenesis. Here, we explore the influence of FCRL3 on B-cell responses to innate TLR9 stimulation. A detailed survey of blood B-cell populations found that FCRL3 expression increased as a function of differentiation and was higher among memory subsets with innate-like features. FCRL3 ligation augmented CpG oligodeoxynucleotide TLR9-mediated B-cell proliferation, activation, and survival, but surprisingly, abrogated plasma cell differentiation and antibody production. Although FCRL3 amplified the NF-κB and mitogen-activated protein kinase signaling cascades, it halted CpG triggered BLIMP1 induction in an ERK-dependent fashion. These findings indicate that FCRL3 differentially modulates innate signaling in B cells and provide new insight into the potential of this disease-associated receptor to counter-regulate adaptive and innate immunity.
Fc 受体样（FCRL）分子优先在 B 淋巴细胞中表达，并具有基于酪氨酸的免疫调节功能。尽管它们通常抑制 B 细胞受体信号，但它们对其他激活途径的影响在很大程度上仍未得到探索。在人类中，FCRL3 编码一种 I 型跨膜蛋白，同时具有胞质 ITAM 和 ITIM 元件，可抑制 B 细胞受体的激活。尽管具有这种抑制特性，但越来越多的证据表明 FCRL3 与自身免疫和淋巴增殖性疾病有关，这表明它在促进 B 细胞发病机制中起作用。在这里，我们研究了 FCRL3 对 B 细胞对先天 TLR9 刺激的反应的影响。对血液 B 细胞群体的详细调查发现，FCRL3 的表达随着分化而增加，并且在具有先天样特征的记忆亚群中更高。FCRL3 交联增强了 CpG 寡脱氧核苷酸 TLR9 介导的 B 细胞增殖、激活和存活，但令人惊讶的是，它取消了浆细胞分化和抗体产生。尽管 FCRL3 放大了 NF-κB 和丝裂原活化蛋白激酶信号级联，但它以 ERK 依赖性的方式阻止了 CpG 触发的 BLIMP1 诱导。这些发现表明，FCRL3 以不同的方式调节 B 细胞中的先天信号，并为这种与疾病相关的受体调节适应性和先天免疫的潜力提供了新的见解。
