Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
J Autoimmun. 2018 May;89:139-148. doi: 10.1016/j.jaut.2017.12.013. Epub 2018 Feb 1.
Regulatory T cells are critical for the generation and maintenance of peripheral tolerance. Conditional deletion of the transcriptional repressor NKAP in Tregs using Foxp3-YFP-cre NKAP conditional knockout mice causes aggressive autoimmunity characterized by thymic atrophy, lymphadenopathy, peripheral T cell activation, generation of autoantibodies, immune infiltration into several organs, and crusty skin at 3 weeks of age, similar to that of "scurfy" Foxp3-mutant mice. While Treg development in the thymus proceeds normally in the absence of NKAP, there is a severe loss of thymically-derived Tregs in the periphery. NKAP-deficient Tregs have a recent thymic emigrant phenotype, and are attacked by complement in a cell-intrinsic manner in the periphery. Previously, we demonstrated that NKAP is required for conventional T cell maturation as it prevents complement-mediated attack in the periphery. We now show that Tregs undergo a similar maturation process as conventional T cells, requiring NKAP to acquire complement resistance after thymic egress.
调节性 T 细胞对于外周耐受的产生和维持至关重要。使用 Foxp3-YFP-cre NKAP 条件性敲除小鼠对 Tregs 中的转录抑制因子 NKAP 进行条件性缺失，导致强烈的自身免疫，其特征是胸腺萎缩、淋巴结病、外周 T 细胞活化、自身抗体产生、免疫浸润到多个器官和 3 周龄时皮肤结痂，类似于“scurfy”Foxp3 突变小鼠。虽然在缺乏 NKAP 的情况下 Treg 在胸腺中的发育正常，但在外周中存在严重的胸腺来源的 Treg 丧失。NKAP 缺陷型 Treg 具有近期胸腺移居表型，并且在外周以细胞内方式被补体攻击。以前，我们证明 NKAP 是常规 T 细胞成熟所必需的，因为它可以防止补体在外周的攻击。我们现在表明 Tregs 经历与常规 T 细胞相似的成熟过程，在离开胸腺后需要 NKAP 获得补体抗性。
