Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
Clin Exp Immunol. 2018 Feb;191(2):151-165. doi: 10.1111/cei.13066. Epub 2017 Nov 20.
Defining how self-antigens are perceived by the immune system is pivotal to understand how tolerance is maintained under homeostatic conditions. Clinically relevant, natural autoantigens targeted by autoantibodies, in e.g. systemic lupus erythematosus (SLE), commonly have an intrinsic ability to engage not only the B cell receptor (BCR), but also a co-stimulatory pathway in B cells, such as the Toll-like receptor (TLR)-7 pathway. Here we developed a novel mouse model displaying inducible expression of a fluorescent epidermal neo-autoantigen carrying an OT-II T cell epitope, B cell antigen and associated ribonucleic acids capable of stimulating TLR-7. The neo-autoantigen was expressed in skin, but did not drain in intact form into draining lymph nodes, even after ultraviolet B (UVB)-stimulated induction of apoptosis in the basal layer. Adoptively transferred autoreactive B cells were excluded follicularly and perished at the T-B border in the spleen, preventing their recirculation and encounter with antigen peripherally. This transitional check-point was bypassed by crossing the reporter to a BCR knock-in line on a C4-deficient background. Adoptively transferred OT-II T cells homed rapidly into cutaneous lymph nodes and up-regulated CD69. Surprisingly, however, tolerance was not broken, as the T cells subsequently down-regulated activation markers and contracted. Our results highlight how sequestration of intracellular and peripheral antigen, the transitional B cell tolerance check-point and T cell regulation co-operate to maintain immunological tolerance in vivo.
确定自身抗原如何被免疫系统识别对于理解在稳态条件下如何维持耐受至关重要。在临床上相关的情况下,自身抗体靶向的天然自身抗原,例如在系统性红斑狼疮 (SLE) 中,通常具有内在的能力,不仅可以与 B 细胞受体 (BCR) 结合,还可以与 B 细胞中的共刺激途径(例如 Toll 样受体 (TLR)-7 途径)结合。在这里,我们开发了一种新型小鼠模型,该模型可诱导表达带有 OT-II T 细胞表位、B 细胞抗原和相关核糖核酸的荧光表皮新自身抗原,这些 RNA 能够刺激 TLR-7。新自身抗原在皮肤中表达,但即使在基底细胞经紫外线 B (UVB) 诱导凋亡后,也不会以完整形式引流到引流淋巴结中。过继转移的自身反应性 B 细胞被滤泡性排除,并在脾脏的 T-B 边界处死亡,从而防止它们在外周循环和与抗原相遇。通过将报告基因与 C4 缺陷背景下的 BCR 敲入系交叉,可绕过此过渡检查点。过继转移的 OT-II T 细胞迅速归巢到皮肤淋巴结,并上调 CD69。然而,令人惊讶的是,耐受并未被打破,因为 T 细胞随后下调了激活标志物并收缩。我们的结果强调了细胞内和外周抗原的隔离、过渡 B 细胞耐受检查点和 T 细胞调节如何共同在体内维持免疫耐受。