Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
J Immunol. 2012 Jul 1;189(1):464-74. doi: 10.4049/jimmunol.1200886. Epub 2012 May 30.
Regulatory T cells (Tregs), in particular CD4(+) Foxp3(+) T cells, have been shown to play an important role in the maintenance of tolerance after allogeneic stem cell transplantation. In the current study, we have identified a population of CD8(+) Foxp3(+) T cells that are induced early during graft-versus-host disease (GVHD), constitute a significant percentage of the entire Treg population, and are present in all major GVHD target organs. These cells expressed many of the same cell surface molecules as found on CD4(+) Tregs and potently suppressed in vitro alloreactive T cell responses. Induction of these cells correlated positively with the degree of MHC disparity between donor and recipient and was significantly greater than that observed for CD4(+)-induced Tregs (iTregs) in nearly all tissue sites. Mice that lacked the ability to make both CD8(+) and CD4(+) iTregs had accelerated GVHD mortality compared with animals that were competent to make both iTreg populations. The absence of both iTreg populations was associated with significantly greater expansion of activated donor T cells and increased numbers of CD4(+) and CD8(+) T cells that secreted IFN-γ and IL-17. The presence of CD8(+) iTregs, however, was sufficient to prevent increased GVHD mortality in the complete absence of CD4(+) Tregs, indicating at least one functional iTreg population was sufficient to prevent an exacerbation in GVHD severity, and that CD8(+) iTregs could compensate for CD4(+) iTregs. These studies define a novel population of CD8(+) Tregs that play a role in mitigating the severity of GVHD after allogeneic stem cell transplantation.
调节性 T 细胞（Tregs），特别是 CD4(+)Foxp3(+)T 细胞，已被证明在同种异体干细胞移植后维持耐受中发挥重要作用。在本研究中，我们鉴定了一群在移植物抗宿主病（GVHD）早期诱导的 CD8(+)Foxp3(+)T 细胞，构成了整个 Treg 群体的重要部分，并存在于所有主要的 GVHD 靶器官中。这些细胞表达了许多与 CD4(+)Tregs 相同的细胞表面分子，并能有效地抑制体外同种反应性 T 细胞反应。这些细胞的诱导与供体和受者之间 MHC 差异的程度呈正相关，并且在几乎所有组织部位的 CD4(+)-诱导的 Tregs（iTregs）观察到的程度都显著更大。与能够产生两种 iTreg 群体的动物相比，缺乏产生 CD8(+)和 CD4(+)iTreg 能力的小鼠的 GVHD 死亡率更高。两种 iTreg 群体的缺失与激活的供体 T 细胞的显著扩增以及分泌 IFN-γ 和 IL-17 的 CD4(+)和 CD8(+)T 细胞数量的增加相关。然而，CD8(+)iTregs 的存在足以在完全缺乏 CD4(+)Tregs 的情况下防止 GVHD 死亡率增加，表明至少有一种功能性 iTreg 群体足以防止 GVHD 严重程度的恶化，并且 CD8(+)iTregs 可以补偿 CD4(+)iTregs。这些研究定义了一种新型的 CD8(+)Treg 群体，它们在同种异体干细胞移植后减轻 GVHD 的严重程度中发挥作用。
