Fukao Saori, Haniuda Kei, Nojima Takuya, Takai Toshiyuki, Kitamura Daisuke
Division of Molecular Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan; and.
Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi 980-8575, Japan.
J Immunol. 2014 Jul 15;193(2):635-44. doi: 10.4049/jimmunol.1302772. Epub 2014 Jun 16.
The rapid Ab responses observed after primary and secondary immunizations are mainly derived from marginal zone (MZ) and memory B cells, respectively, but it is largely unknown how these responses are negatively regulated. Several inhibitory receptors have been identified and their roles have been studied, but mainly on follicular B cells and much less so on MZ B, and never on memory B cells. gp49B is an Ig superfamily member that contains two ITIMs in its cytoplasmic tail, and it has been shown to negatively regulate mast cell, macrophage, and NK cell responses. In this study, we demonstrate that gp49B is preferentially expressed on memory and MZ B cells. We show that gp49B(-/-) mice produce more IgM after a primary immunization and more IgM and IgG1 after a secondary immunization than gp49B(+/+) mice in T cell-dependent immune responses. Memory and MZ B cells from gp49B(-/-) mice also produce more Abs upon in vitro stimulation with CD40 than those from gp49B(+/+) mice. The in vitro IgM production by MZ B cells from gp49B(+/+), but not gp49B(-/-), mice is suppressed by interaction with a putative gp49B ligand, the integrin αvβ3 heterodimer. In addition, gp49B(-/-) mice exhibited exaggerated IgE production in the memory recall response. These results suggest that plasma cell development from memory and MZ B cells, as well as subsequent Ab production, are suppressed via gp49B. In memory B cells, this suppression also prevents excessive IgE production, thus curtailing allergic diseases.
初次和二次免疫后观察到的快速抗体反应分别主要源自边缘区（MZ）B细胞和记忆B细胞，但这些反应如何受到负调控在很大程度上尚不清楚。已鉴定出几种抑制性受体并研究了它们的作用，但主要是在滤泡B细胞上，在MZ B细胞上的研究较少，而在记忆B细胞上从未有过研究。gp49B是免疫球蛋白超家族成员，其胞质尾部含有两个免疫受体酪氨酸抑制基序（ITIM），并且已证明它对肥大细胞、巨噬细胞和自然杀伤（NK）细胞反应具有负调控作用。在本研究中，我们证明gp49B在记忆B细胞和MZ B细胞上优先表达。我们发现，在T细胞依赖性免疫反应中，与野生型（gp49B(+/+)）小鼠相比，基因敲除型（gp49B(-/-)）小鼠在初次免疫后产生更多IgM，在二次免疫后产生更多IgM和IgG1。来自gp49B(-/-)小鼠的记忆B细胞和MZ B细胞在体外经CD40刺激后也比来自gp49B(+/+)小鼠的细胞产生更多抗体。野生型小鼠MZ B细胞的体外IgM产生，但基因敲除型小鼠的不产生，被与假定的gp49B配体整合素αvβ3异二聚体的相互作用所抑制。此外，gp49B(-/-)小鼠在记忆回忆反应中表现出过度的IgE产生。这些结果表明，记忆B细胞和MZ B细胞向浆细胞的发育以及随后的抗体产生通过gp49B受到抑制。在记忆B细胞中，这种抑制还可防止过度的IgE产生，从而减少过敏性疾病。
