Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Immunity. 2012 Aug 24;37(2):209-22. doi: 10.1016/j.immuni.2012.05.027.
Acute graft-versus-host disease (GvHD) is a major cause of mortality in allogeneic bone marrow transplantation (BMT), for which administration of FoxP3(+) regulatory T (Treg) cells has been proposed as a therapy. However, the phenotypic stability of Treg cells is controversial, and STAT3-dependent cytokines can inhibit FoxP3 expression. We assessed whether the elimination of STAT3 in T cells could limit the severity of GvHD. We found STAT3 limited FoxP3(+) Treg cell numbers following allogeneic BMT by two pathways: instability of natural Treg (nTreg) cells and inhibition of induced Treg (iTreg) cell polarization from naive CD4(+) T cells. Deletion of STAT3 within only the nTreg cell population was not sufficient to protect against lethal GvHD. In contrast, transfer of STAT3-deficient naive CD4(+) T cells increased FoxP3(+) Treg cells post-BMT and prevented lethality, suggesting that the consequence of STAT3 signaling may be greater for iTreg rather than nTreg cells during GvHD.
急性移植物抗宿主病 (GvHD) 是异基因骨髓移植 (BMT) 患者死亡的主要原因，已有研究提出，FoxP3(+)调节性 T (Treg) 细胞的输注可能是一种有效的治疗方法。然而，Treg 细胞的表型稳定性存在争议，STAT3 依赖性细胞因子可抑制 FoxP3 的表达。我们评估了 T 细胞中 STAT3 的缺失是否可以限制 GvHD 的严重程度。我们发现，在异基因 BMT 后，STAT3 通过两种途径限制 FoxP3(+)Treg 细胞的数量：天然 Treg(nTreg)细胞的不稳定性和初始 CD4(+)T 细胞向诱导性 Treg(iTreg)细胞极化的抑制。仅在 nTreg 细胞群中缺失 STAT3 不足以预防致死性 GvHD。相比之下，STAT3 缺陷的初始 CD4(+)T 细胞的转移增加了 BMT 后 FoxP3(+)Treg 细胞的数量，并预防了致死性，这表明在 GvHD 期间，STAT3 信号的后果可能对 iTreg 细胞比对 nTreg 细胞更大。
