Park Mi Young, Sudan Raki, Srivastava Neetu, Neelam Sudha, Youngs Christie, Wang Jia-Wang, Engelman Robert W, Kerr William G
Department of Microbiology &Immunology, SUNY Upstate Medical University, Syracuse, NY, US.
Department of Internal Medicine, University of South Florida, Tampa, Florida, US.
Sci Rep. 2016 Nov 8;6:36568. doi: 10.1038/srep36568.
The PH-BEACH-WD40 (PBW) protein family members play a role in coordinating receptor signaling and intracellular vesicle trafficking. LPS-Responsive-Beige-like Anchor (LRBA) is a PBW protein whose immune function remains elusive. Here we show that LRBA-null mice are viable, but exhibit compromised rejection of allogeneic, xenogeneic and missing self bone-marrow grafts. Further, we demonstrate that LRBA-null Natural Killer (NK) cells exhibit impaired signaling by the key NK activating receptors, NKp46 and NKG2D. However, induction of IFN-γ by cytokines remains intact, indicating LRBA selectively facilitates signals by receptors for ligands expressed on the surface of NK targets. Surprisingly, LRBA limits immunoregulatory cell numbers in tissues where GvHD is primed or initiated, and consistent with this LRBA-null mice also demonstrate resistance to lethal GvHD. These findings demonstrate that LRBA is redundant for host longevity while being essential for both host and donor-mediated immune responses and thus represents a unique and novel molecular target in transplant immunology.
PH-BEACH-WD40（PBW）蛋白家族成员在协调受体信号传导和细胞内囊泡运输中发挥作用。脂多糖反应性米色样锚定蛋白（LRBA）是一种PBW蛋白，其免疫功能尚不清楚。在此我们表明，LRBA基因敲除小鼠是存活的，但对同种异体、异种和自身缺失的骨髓移植物的排斥反应受损。此外，我们证明LRBA基因敲除的自然杀伤（NK）细胞通过关键的NK激活受体NKp46和NKG2D表现出信号传导受损。然而，细胞因子诱导的IFN-γ仍然正常，表明LRBA选择性地促进NK靶标表面表达的配体受体的信号传导。令人惊讶的是，LRBA限制了移植物抗宿主病（GvHD）引发或启动部位组织中的免疫调节细胞数量，与此一致的是，LRBA基因敲除小鼠也表现出对致死性GvHD的抗性。这些发现表明，LRBA对宿主寿命而言是多余的，而对宿主和供体介导的免疫反应都是必不可少的，因此代表了移植免疫学中一个独特的新型分子靶点。
