Department of Medicine, UCSD, La Jolla, California, USA.
J Clin Invest. 2010 Feb;120(2):570-81. doi: 10.1172/JCI40055. Epub 2010 Jan 4.
TLRs sense various microbial products. Their function has been best characterized in DCs and macrophages, where they act as important mediators of innate immunity. TLR4 is also expressed on CD4+ T cells, but its physiological function on these cells remains unknown. Here, we have shown that TLR4 triggering on CD4+ T cells affects their phenotype and their ability to provoke intestinal inflammation. In a model of spontaneous colitis, Il10-/-Tlr4-/- mice displayed accelerated development of disease, with signs of overt colitis as early as 8 weeks of age, when compared with Il10-/- and Il10-/-Tlr9-/- mice, which did not develop colitis by 8 months. Similar results were obtained in a second model of colitis in which transfer of naive Il10-/-Tlr4-/- CD4+ T cells into Rag1-/- recipients sufficient for both IL-10 and TLR4 induced more aggressive colitis than the transfer of naive Il10-/- CD4+ T cells. Mechanistically, LPS stimulation of TLR4-bearing CD4+ T cells inhibited ERK1/2 activation upon subsequent TCR stimulation via the induction of MAPK phosphatase 3 (MKP-3). Our data therefore reveal a tonic inhibitory role for TLR4 signaling on subsequent TCR-dependent CD4+ T cell responses.
TLRs 能够感知各种微生物产物。它们在 DC 和巨噬细胞中的功能已得到充分研究，在这些细胞中，它们是先天免疫的重要介质。TLR4 也在 CD4+T 细胞上表达，但它在这些细胞上的生理功能尚不清楚。在这里，我们已经表明，TLR4 在 CD4+T 细胞上的触发会影响其表型及其引发肠道炎症的能力。在自发性结肠炎模型中，与 Il10-/-和 Il10-/-Tlr9-/-小鼠相比，Il10-/-Tlr4-/-小鼠在 8 周龄时就表现出疾病的加速发展，出现明显的结肠炎迹象，而 Il10-/-和 Il10-/-Tlr9-/-小鼠在 8 个月时并未发生结肠炎。在另一种结肠炎模型中也得到了类似的结果，其中将幼稚的 Il10-/-Tlr4-/-CD4+T 细胞转移到 Rag1-/-受体中，这些受体足以同时诱导 IL-10 和 TLR4，导致更具侵袭性的结肠炎，而不是转移幼稚的 Il10-/-CD4+T 细胞。从机制上讲，TLR4 配体 LPS 刺激 TLR4 携带的 CD4+T 细胞会通过诱导丝裂原活化蛋白激酶磷酸酶 3（MKP-3）抑制随后 TCR 刺激时的 ERK1/2 激活。因此，我们的数据揭示了 TLR4 信号在随后的 TCR 依赖性 CD4+T 细胞反应中的抑制性作用。
