Neuroinflammation Unit, Department of Clinical Sciences, University of Lund, Lund, Sweden.
J Immunol. 2010 Jul 1;185(1):345-56. doi: 10.4049/jimmunol.0901693. Epub 2010 Jun 4.
A protective and anti-inflammatory role for CD1d-dependent NKT cells (NKTs) has been reported in experimental and human autoimmune diseases. However, their role in arthritis has been unclear, with conflicting reports of CD1d-dependent NKTs acting both as regulatory and disease-promoting cells in arthritis. These differing modes of action might be due to genetic differences of inbred mice and incomplete backcrossing of gene-modified mice. We therefore put special emphasis on controlling the genetic backgrounds of the mice used. Additionally, we used two different murine arthritis models, Ag-induced arthritis (AIA) and collagen-induced arthritis (CIA), to evaluate acute and chronic arthritis in CD1d knockout mice and mice depleted of NK1.1(+) cells. CD1d-deficient mice developed more severe AIA compared with wild-type littermates, with a higher degree of inflammation and proteoglycan depletion. Chronic arthritis in CIA was also worse in the absence of CD1d-dependent NKTs. Elevated levels of Ag-specific IFN-gamma production accompanied these findings rather than changes in IL-17alpha. Depletion of NK1.1(+) cells supported these findings in AIA and CIA. This report provides support for CD1d-dependent NKTs being suppressor cells in acute and chronic arthritis, likely via inhibition of arthritogenic Th1 cells. These results make CD1d-dependent NKTs an attractive target for therapeutic intervention.
已报道 CD1d 依赖性自然杀伤 T 细胞（NKT 细胞）在实验性和人类自身免疫性疾病中具有保护和抗炎作用。然而，它们在关节炎中的作用尚不清楚，有报道称 CD1d 依赖性 NKT 细胞在关节炎中既作为调节细胞又作为促进疾病的细胞发挥作用。这些不同的作用模式可能是由于近交系小鼠的遗传差异和基因修饰小鼠的不完全回交。因此，我们特别强调控制所用小鼠的遗传背景。此外，我们使用了两种不同的小鼠关节炎模型，即抗原诱导性关节炎（AIA）和胶原诱导性关节炎（CIA），以评估 CD1d 敲除小鼠和 NK1.1（+）细胞耗竭小鼠的急性和慢性关节炎。与野生型同窝仔相比，CD1d 缺陷型小鼠发生更严重的 AIA，炎症和蛋白聚糖耗竭程度更高。在没有 CD1d 依赖性 NKT 细胞的情况下，慢性 CIA 关节炎也更严重。这些发现伴随着 Ag 特异性 IFN-γ产生水平的升高，而不是 IL-17alpha 的变化。在 AIA 和 CIA 中 NK1.1（+）细胞的耗竭支持了这些发现。本报告为 CD1d 依赖性 NKT 细胞在急性和慢性关节炎中作为抑制细胞提供了支持，可能通过抑制致关节炎性 Th1 细胞。这些结果使 CD1d 依赖性 NKT 细胞成为治疗干预的有吸引力的靶点。
