Schuetz C, Lee K M, Scott R, Kojima L, Washburn L, Liu L, Liu W-H, Tector H, Lei J, Yeh H, Kim J I, Markmann J F
Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Boston, MA.
Am J Transplant. 2017 Jun;17(6):1656-1662. doi: 10.1111/ajt.14265. Epub 2017 Apr 11.
Immunologic tolerance to solid organ and islet cell grafts has been achieved in various rodent models by using antibodies directed at CD45RB and Tim-1. We have shown that this form of tolerance depends on regulatory B cells (Bregs). To elucidate further the mechanism by which Bregs induce tolerance, we investigated the requirement of natural killer (NK) and NKT cells in this model. To do so, hyperglycemic B6, μMT, Beige, or CD1d mice received BALB/c islet grafts and treatment with the tolerance-inducing regimen consisting of anti-CD45RB and anti-TIM1. B6 mice depleted of both NK and NKT cells by anti-NK1.1 antibody and mice deficient in NK activity (Beige) did not develop tolerance after dual-antibody treatment. In contrast, transplant tolerance induction was successful in CD1d recipients (deficient in NKT cells), indicating that NK, but not NKT, cells are essential in B cell-dependent tolerance. In addition, reconstitution of Beige host with NK cells restored the ability to induce transplant tolerance with dual-antibody treatment. Transfer of tolerance by B cells from tolerant mice was also dependent on host Nk1.1 cells. In conclusion, these results show that regulatory function of B cells is dependent on NK cells in this model of transplantation tolerance.
通过使用针对CD45RB和Tim-1的抗体，在各种啮齿动物模型中已实现对实体器官和胰岛细胞移植的免疫耐受。我们已经表明，这种耐受形式依赖于调节性B细胞（Bregs）。为了进一步阐明Bregs诱导耐受的机制，我们在该模型中研究了自然杀伤（NK）细胞和自然杀伤T（NKT）细胞的需求。为此，高血糖的B6、μMT、米色或CD1d小鼠接受了BALB/c胰岛移植，并采用由抗CD45RB和抗TIM1组成的耐受诱导方案进行治疗。用抗NK1.1抗体耗尽NK和NKT细胞的B6小鼠以及NK活性缺陷的小鼠（米色）在双抗体治疗后未产生耐受。相反，在CD1d受体（缺乏NKT细胞）中移植耐受诱导成功，表明NK细胞而非NKT细胞在B细胞依赖性耐受中至关重要。此外，用NK细胞重建米色宿主恢复了用双抗体治疗诱导移植耐受的能力。来自耐受小鼠的B细胞的耐受转移也依赖于宿主Nk1.1细胞。总之，这些结果表明，在该移植耐受模型中，B细胞的调节功能依赖于NK细胞。
