Autoimmune Memory T Helper 17 Cell Function and Expansion Are Dependent on Interleukin-23
Autoimmune Memory T Helper 17 Cell Function and Expansion Are Dependent on Interleukin-23
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DOI：
10.1016/j.celrep.2013.03.035
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发表时间：
2013-05-01
期刊：
影响因子：
8.8
通讯作者：
McGeachy, Mandy J.
中科院分区：
文献类型：
--
作者：
Haines, Christopher J.;Chen, Yi;McGeachy, Mandy J.
白细胞介素-23 （IL-23）对致病性T辅助17 （Th17）细胞的分化至关重要，但其在记忆性Th17细胞反应中的作用尚不清楚。利用实验性自身免疫性脑脊髓炎（EAE）模型，我们报告了记忆性Th17细胞在再挑战下迅速扩增并大量迁移到中枢神经系统，导致临床疾病的早期发病和严重程度增加。记忆Th17细胞是由IL-17（+）和ROR γ t（+）前体产生的，Th17细胞表型的稳定性取决于初始反应的时间。这种增强的召回反应需要IL-23。IL-23受体阻断并不直接影响IL-17的产生，但确实损害了随后的增殖和共表达Th1细胞特异性转录因子T-bet的效应物的产生。此外，在缺乏IL-23信号的Th17细胞中，许多细胞周期进程所需的基因被下调，这表明IL-23在原发性和记忆性Th17细胞反应中的主要机制是通过调节增殖相关途径运作的。
Interleukin-23 (IL-23) is essential for the differentiation of pathogenic effector T helper 17 (Th17) cells, but its role in memory Th17 cell responses is unclear. Using the experimental autoimmune encephalomyelitis (EAE) model, we report that memory Th17 cells rapidly expanded in response to rechallenge and migrated to the CNS in high numbers, resulting in earlier onset and increased severity of clinical disease. Memory Th17 cells were generated from IL-17(+) and ROR gamma t(+) precursors, and the stability of the Th17 cell phenotype depended on the amount of time allowed for the primary response. IL-23 was required for this enhanced recall response. IL-23 receptor blockade did not directly impact IL-17 production, but did impair the subsequent proliferation and generation of effectors coexpressing the Th1 cell-specific transcription factor T-bet. In addition, many genes required for cell-cycle progression were downregulated in Th17 cells that lacked IL-23 signaling, showing that a major mechanism for IL-23 in primary and memory Th17 cell responses operates via regulation of proliferation-associated pathways.