IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation
IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation
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DOI：
10.1182/blood-2009-05-221135
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发表时间：
2009-12-17
期刊：
影响因子：
20.3
通讯作者：
Blazar, Bruce R.
中科院分区：
文献类型：
--
作者：
Bucher, Christoph;Koch, Lisa;Blazar, Bruce R.
白细胞介素-21（IL-21）增强辅助性T细胞1（Th 1）和Th 17分化，同时抑制诱导型调节性T细胞（TCR 4）从初始T细胞的转化。为了确定IL-21在移植物抗宿主病（GVHD）中的作用，将抗IL-21抗体（Ab）给予CD 25（-）CD 4（+）或CD 4（+）和CD 8（+）T效应物受体。IL-21中和作用减弱了GVHD相关的体重减轻并延长了生存期。同样，大多数接受IL-21（-/-）CD 25（-）T效应子的小鼠长期存活，而接受野生型T细胞的小鼠死亡。后者受体在回肠和结肠中具有较高等级的GVHD。令人惊讶的是，IL-21信号传导的破坏并不影响IL-17的产生，尽管结肠浸润性T效应细胞具有降低的干扰素γ（IFN γ）和增加的IL-4产生。在抗IL-21 Ab处理的FoxP 3（-）IL-21（-/-）T细胞受体的结肠中，FoxP 3（+）Treg增加，表明Treg转化。从嵌合体中分离的FoxP 3缺陷T效应子的接受者对IL-21阻断的GVHD保护作用具有抗性。而移植物抗白血病（GVL）可以发生在IL-21的情况下，IL-21和穿孔素表达的损失废除GVL。总之，这些数据表明IL-21抑制诱导型Treg转化，并进一步表明IL-21阻断是减少GVHD诱导的损伤的有吸引力的策略。（血。2009; 114：5375-5384）
Interleukin-21 (IL-21) enhances T helper 1 (Th1) and Th17 differentiation while inhibiting the conversion of inducible regulatory T cells (Tregs) from naive T cells. To determine the role of IL-21 in graft-versus-host disease (GVHD), anti-IL-21 antibody (Ab) was given to recipients of CD25(-)CD4(+) or CD4(+) and CD8(+) T-effectors. IL-21 neutralization attenuated GVHD-related weight loss and prolonged survival. Likewise, a majority of mice receiving IL-21(-/-) CD25(-) T-effectors survived long term, whereas those receiving wild-type T cells died. The latter recipients had higher grades of GVHD in the ileum and colon. Surprisingly, disruption of IL-21 signaling did not affect IL-17 production, although colon-infiltrating T-effector cells had decreased interferon gamma (IFN gamma) and increased IL-4 production. FoxP3(+) Tregs were increased in colons of anti-IL-21 Ab-treated recipients of FoxP3(-) IL-21(-/-) T cells, indicating Treg conversion. Recipients of FoxP3-deficient T-effectors isolated from chimeras were resistant to the GVHD protective effects of IL-21 blockade. Whereas graft-versus-leukemia (GVL) can occur in the absence of IL-21, loss of both IL-21 and perforin expression abrogated GVL. Together, these data indicate that IL-21 suppresses inducible Treg conversion and further suggest that IL-21 blockade is an attractive strategy to reduce GVHD-induced injury. (Blood. 2009; 114: 5375-5384)