Pathogen-Host Interaction Group, Division of Clinical Medicine, Brighton and Sussex Medical School, Falmer, United Kingdom.
J Immunol. 2010 Dec 1;185(11):6591-8. doi: 10.4049/jimmunol.1002416. Epub 2010 Nov 3.
Bacterial superantigens are potent T cell activators. In humans they cause toxic shock and scarlet fever, and they are implicated in Kawasaki's disease, autoimmunity, atopy, and sepsis. Their function remains unknown, but it may be to impair host immune responses increasing bacterial carriage and transmission. Regulatory (CD25(+)FOXP3(+)) T cells (Tregs) play a role in controlling inflammatory responses to infection. Approximately 2% of circulating T cells are naturally occurring Tregs (nTregs). Conventional Ag stimulation of naive FOXP3(-) T cells induces Ag-specific Tregs. Polyclonal T cell activation has been shown to produce non-Ag-specific Tregs. Because superantigens are unique among microbial virulence factors in their ability to trigger polyclonal T cell activation, we wanted to determine whether superantigen stimulation of T cells could induce non-Ag-specific Tregs. We assessed the effect of superantigen stimulation of human T cells on activation, regulatory markers, and cytokine production by flow cytometry and T cell suppression assays. Stimulation of PBMCs with staphylococcal exotoxin A and streptococcal pyrogenic exotoxins A and K/L resulted in dose-dependent FOXP3 expression. Characterization of this response for streptococcal pyrogenic exotoxin K/L confirmed its Vβ specificity, that CD25(+)FOXP3(+) cells arose from CD25(-) T cells and required APCs. These cells had increased CTLA-4 and CD127 expression, typical of the recently described activated converted Treg-like cells, and exhibited functional suppressor activity comparable to nTregs. Superantigen-stimulated CD25(+)FOXP3(+) T cells expressed IL-10 at lower superantigen concentrations than was required to trigger IFN-γ production. This study provides a mechanism for bacterial evasion of the immune response through the superantigen induction of Tregs.
细菌超抗原是强有力的 T 细胞激活物。在人类中，它们导致中毒性休克和猩红热，并且与川崎病、自身免疫、过敏和败血症有关。它们的功能尚不清楚，但可能是削弱宿主的免疫反应，增加细菌携带和传播。调节性（CD25(+)FOXP3(+））T 细胞（Tregs）在控制感染引起的炎症反应中发挥作用。大约 2%的循环 T 细胞是天然存在的 Tregs（nTregs）。幼稚 FOXP3(-)T 细胞的常规 Ag 刺激诱导 Ag 特异性 Tregs。多克隆 T 细胞激活已被证明产生非 Ag 特异性 Tregs。由于超抗原在其引发多克隆 T 细胞激活的能力方面是微生物毒力因子中独一无二的，因此我们想确定超抗原刺激 T 细胞是否可以诱导非 Ag 特异性 Tregs。我们通过流式细胞术和 T 细胞抑制测定评估了超抗原刺激人 T 细胞对 T 细胞激活、调节标记物和细胞因子产生的影响。葡萄球菌肠毒素 A 和链球菌致热外毒素 A 和 K/L 对 PBMC 的刺激导致 FOXP3 表达呈剂量依赖性。对链球菌致热外毒素 K/L 的这种反应的特征描述证实了其 Vβ 特异性，即 CD25(+)FOXP3(+)细胞源自 CD25(-)T 细胞，并且需要 APC。这些细胞表达 CTLA-4 和 CD127 增加，具有最近描述的激活转化的 Treg 样细胞的特征，并表现出与 nTregs 相当的功能性抑制活性。超抗原刺激的 CD25(+)FOXP3(+)T 细胞在较低的超抗原浓度下表达 IL-10，低于触发 IFN-γ产生所需的浓度。这项研究为细菌通过超抗原诱导 Tregs 逃避免疫反应提供了一种机制。
