Control of autoimmune myocarditis and multiorgan inflammation by glucocorticoid-induced TNF receptor family-related protein high, Foxp3-expressing CD25+ and CD25- regulatory T cells
Control of autoimmune myocarditis and multiorgan inflammation by glucocorticoid-induced TNF receptor family-related protein high, Foxp3-expressing CD25+ and CD25- regulatory T cells
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DOI：
10.4049/jimmunol.176.8.4748
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发表时间：
2006-04-15
影响因子：
4.4
通讯作者：
Sakaguchi, Shimon
中科院分区：
文献类型：
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作者：
Ono, Masahiro;Shimizu, Jun;Sakaguchi, Shimon
自然产生的CD4(+)调节性T细胞(Treg)的异常会在人类和啮齿动物中引起严重的自身免疫性/炎症性疾病。转录因子Foxp3是目前天然CD4(+)Treg最特异的标志物，但如果能阐明其他Treg标志物，特别是细胞表面分子，它将是有用的。我们在这项研究中证明，绝大多数表达Foxp3的CD4(+)T细胞(无论是CD25(+)还是CD25(-))都显示出糖皮质激素诱导的TNFR家族相关基因/蛋白(GITR)的结构性高表达。转移去除GITR(高)细胞的T细胞或胸腺细胞悬液在BALB/c裸鼠中产生比仅去除CD25(+)CD4(+)T细胞的类似细胞悬液转移更广泛和更严重的自身免疫性疾病。值得注意的是，接受GITR(高)群体耗尽细胞的小鼠会出现严重的多器官炎症，包括类似于人类巨细胞性心肌炎的致命性自身免疫性心肌炎，并伴有高效价抗肌球蛋白自身抗体。类似地，将GITR(高)耗尽细胞从糖尿病前期NOD小鼠转移到NOD-SCID小鼠会加速糖尿病的发展，并诱导骨骼肌炎和其他自身免疫性/炎症性疾病。我们的结论是，GITR高表达Foxp3的自然Treg包含CD25(+)和CD25(-)细胞群，有助于预防各种自身免疫性/炎症性疾病，这些细胞的耗尽允许激活甚至微弱或罕见的自身反应性T细胞，从而导致广泛的严重自身免疫性疾病。以这种方式诱发的疾病包括许多在没有太多证据的情况下被怀疑是人类自身免疫病因的疾病。GITR(高)、Foxp3表达的天然Treg是治疗和预防这些疾病的潜在靶点。
Anomalies of naturally occurring CD4(+) regulatory T cells (Treg) cause severe autoimmune/inflammatory diseases in humans and rodents. The transcription factor Foxp3 is currently the most specific marker for natural CD4(+) Treg, but it would be useful if other Treg markers, particularly cell surface molecules, could be elucidated. We demonstrate in this study that the vast majority of Foxp3-expressing CD4(+) T cells (whether CD25(+) or CD25(-)) show constitutive high-level expression of glucocorticoid-induced TNFR family-related gene/protein (GITR). Transfer of T cell or thymocyte suspensions depleted of GITR(high) cells produces in BALB/c nude mice a wider spectrum and more severe forms of autoimmune diseases than does transfer of similar cell suspensions depleted of CD25(+)CD4(+) T cells only. Notably, mice that receive cells depleted of GITR(high) populations develop severe multiorgan inflammation that includes fatal autoimmune myocarditis resembling giant cell myocarditis in humans, accompanying high-titer anti-myosin autoantibodies. Similar transfer of GITR(high)-depleted cells from prediabetic NOD mice to NOD-SCID mice accelerates the development of diabetes and induces skeletal muscle myositis and other autoimmune/inflammatory diseases. We conclude that GITR high, Foxp3-expressing natural Treg, containing both CD25(+) and CD25(-) cell populations, contribute to preventing a variety of autoimmune/inflammatory diseases, and depletion of these cells allows the activation of even weak or rare autoreactive T cells yielding widespread severe autoimmune disease. Diseases induced in this way include many which have been suspected of an autoimmune etiology in humans without much evidence. GITR(high), Foxp3-expressing natural Treg represent a potential target for the treatment and prevention of these diseases.