Lenartić Maja, Jelenčić Vedrana, Zafirova Biljana, Ožanič Mateja, Marečić Valentina, Jurković Slaven, Sexl Veronika, Šantić Marina, Wensveen Felix M, Polić Bojan
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia.
Laboratory of Dendritic Cell Immunobiology, Immunology Department, Institute Pasteur, 75015 Paris, France.
J Immunol. 2017 Feb 15;198(4):1531-1542. doi: 10.4049/jimmunol.1600461. Epub 2017 Jan 13.
NKG2D is a potent activating receptor that is expressed on cytotoxic immune cells such as CD8 T and NK cells, where it promotes cytotoxicity after binding stress ligands on infected or transformed cells. On NK cell precursors NKG2D modulates proliferation and maturation. Previously, we observed that NKG2D deficiency affects peripheral B cell numbers. In this study, we show that NKG2D regulates B1a cell development and function. We find that mice deficient for NKG2D have a strong reduction of B1a cell numbers. As a result, NKG2D-deficient mice produce significantly less Ag-specific IgM Abs upon immunization with T cell-independent Ags, and they are more susceptible to Gram-negative sepsis. Klrk1 B1a cells are also functionally impaired and they fail to provide protection against Francisella novicida upon adoptive transfer. Using mixed bone marrow chimeric mice, we show that the impact of NKG2D deficiency on B1a cell development is cell intrinsic. No changes in homeostatic turnover and homing of B cells were detectable, limiting the effects of NKG2D to modulation of the hematopoietic development of B1a cells. Using conditional ablation, we demonstrate that the effect of NKG2D on B1a cell development occurs at a developmental stage that precedes the common lymphoid progenitor. Our findings reveal an unexpected new role for NKG2D in the regulation of B1a cell development. The protective effects of this activating receptor therefore reach beyond that of cytotoxic cells, stimulating the immune system to fight bacterial infections by promoting development of innate-like B cells.
NKG2D是一种强效激活受体，表达于细胞毒性免疫细胞如CD8 T细胞和NK细胞上，在这些细胞中，它与感染或转化细胞上的应激配体结合后可促进细胞毒性。在NK细胞前体上，NKG2D调节增殖和成熟。此前，我们观察到NKG2D缺陷会影响外周B细胞数量。在本研究中，我们表明NKG2D调节B1a细胞的发育和功能。我们发现NKG2D缺陷的小鼠B1a细胞数量大幅减少。因此，用非T细胞依赖性抗原免疫后，NKG2D缺陷的小鼠产生的抗原特异性IgM抗体显著减少，并且它们更易患革兰氏阴性菌败血症。Klrk1 B1a细胞的功能也受损，在过继转移后无法提供针对新凶手弗朗西斯菌的保护。使用混合骨髓嵌合小鼠，我们表明NKG2D缺陷对Bla细胞发育的影响是细胞内在的。未检测到B细胞稳态更新和归巢的变化，将NKG2D的作用限制在对B1a细胞造血发育的调节上。使用条件性消融，我们证明NKG2D对B1a细胞发育的影响发生在常见淋巴样祖细胞之前的发育阶段。我们的发现揭示了NKG2D在B1a细胞发育调节中的一个意想不到的新作用。因此，这种激活受体的保护作用超出了细胞毒性细胞，通过促进先天性样B细胞的发育刺激免疫系统对抗细菌感染。
