Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells.
Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells.
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DOI：
10.1053/j.gastro.2011.05.052
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发表时间：
2011-09
期刊：
影响因子：
29.4
通讯作者：
T. Sujino;T. Kanai;Y. Ono;Y. Mikami;A. Hayashi;Tomomitsu Doi;K. Matsuoka;T. Hisamatsu;H. Takaishi;H. Ogata;A. Yoshimura;D. Littman;T. Hibi
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文献类型：
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作者：
T. Sujino;T. Kanai;Y. Ono;Y. Mikami;A. Hayashi;Tomomitsu Doi;K. Matsuoka;T. Hisamatsu;H. Takaishi;H. Ogata;A. Yoshimura;D. Littman;T. Hibi
背景与目的虽然辅助性T细胞（Th）17和Th 1细胞参与肠道炎症的发病机制，但它们的发育途径和促进疾病的充分性尚不清楚; CD 4 + CD 25+调节性T（T（R））细胞在其发育中的作用也不清楚。方法：采用从类维生素A相关孤儿受体γ t（RORγt）gfp/GFP或Ly5.1/Ly5.2同源小鼠中获得的幼稚CD 4 + CD 45 RB（high）T细胞和/或CD 4 + CD 25 + T（R）细胞进行过继转移实验，研究其诱导和抑制结肠炎的作用。结果在大肠杆菌中观察到3种CD 4 + Th 1细胞（白细胞介素[IL]-17 A →干扰素[IFN]-γ γ）：RORγt →直接从初始T细胞分化的经典Th 1细胞; RORγt → Th 1样细胞;和通过Th 17从RORγt β细胞终末分化的ROR γt β替代性Th 1细胞（IL-17 A → IFN-γ γ γ）、Th 17/Th 1（IL-17 A → IFN-γ γ）或Th 1样（IL-17 A → IFN-γ）细胞。在该途径中，CD 4 + CD 25 + T（R）细胞不仅抑制经典Th 1细胞的发育，而且在Th 17/Th 1向替代Th 1细胞转变时抑制替代Th 1细胞的发育，导致在结肠炎发展受到抑制的小鼠中Th 17和Th 17/Th 1细胞的积累。此外，T（R）细胞调节在结肠炎条件下建立的Th 17和Th 1细胞的平衡，以在非结肠炎条件下产生高的Th 17和Th 17/Th 1细胞与Th 1细胞的比率。结论Th 17和Th 17/Th 1细胞通过Th 17、Th 17/Th 1和Th 1样细胞成为替代性Th 1细胞，独立于经典Th 1细胞。T（R）细胞抑制该途径，导致Th 17和Th 17/Th 1细胞的积累。
BACKGROUND & AIMS Although T-helper (Th) 17 and Th1 cells are involved in pathogenesis of intestinal inflammation, their developmental pathways and sufficiency to promote disease are not known; nor are the roles of CD4⁺CD25⁺ regulatory T (T(R)) cells in their development. METHODS We performed adoptive transfer experiments to investigate the induction and suppression of colitis using naïve CD4⁺CD45RB(high) T cells and/or CD4⁺CD25⁺ T(R) cells that were obtained from retinoid-related orphan receptor gamma t (RORγt) gfp/⁺ or Ly5.1/Ly5.2 congenic mice. RESULTS We observed 3 types of colitogenic CD4⁺ Th1 cells (interleukin [IL]-17A⁻interferon [IFN]-γ⁺): RORγt⁻ classical Th1 cells that differentiated directly from naïve T cells; RORγt⁺ Th1-like cells; and RORγt⁻ alternative Th1 cells that were terminally differentiated from RORγt⁺ cells via Th17 (IL-17A⁺IFN-γ⁻), Th17/Th1 (IL-17A⁺IFN-γ⁺), or Th1-like (IL-17A⁻IFN-γ⁺) cells. In this pathway, CD4⁺CD25⁺ T(R) cells suppress the development of not only classical Th1 cells, but also alternative Th1 cells at the transition of Th17/Th1 into alternative Th1 cells, resulting in accumulation of Th17 and Th17/Th1 cells in mice in which the development of colitis was suppressed. Furthermore, T(R) cells regulated the established balance of Th17 and Th1 cells under colitic conditions to yield a high ratio of Th17 and Th17/Th1 cells to Th1 cells in noncolitic conditions. CONCLUSIONS Th17 and Th17/Th1 cells become colitogenic alternative Th1 cells via Th17, Th17/Th1, and Th1-like cells, independently of classical Th1 cells. T(R) cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells.