Liu Haiying, Komai-Koma Mousa, Xu Damo, Liew Foo Y
Division of Immunology, Infection, and Inflammation, University of Glasgow, Glasgow G11 6NT, United Kingdom.
Proc Natl Acad Sci U S A. 2006 May 2;103(18):7048-53. doi: 10.1073/pnas.0601554103. Epub 2006 Apr 21.
Toll-like receptors (TLRs) are primary sensors of both innate and adaptive immune systems and play a pivotal role in response against structurally conserved components of pathogens. Synthetic bacterial lipoprotein (BLP) Pam3Cys-SK4 is a TLR2 agonist that is capable of modulating T cell immune responses. We show here that BLP, together with anti-CD3 antibody [T cell receptor (TcR) activation], induced proliferation of both CD4+ CD25+ regulatory T cells (Tregs) and CD4+ CD25- (effector) T cells in the absence of antigen-presenting cells. The expanded Tregs showed a transient loss of suppressive activity. Moreover, BLP rendered effectors resistant to the suppression of Tregs by increasing IL-2 secretion. BLP also transiently suppressed the induction of Foxp3 (X-linked forkhead/winged helix transcription factor) mRNA in Tregs at the first 8-15 h after T cell receptor activation. Consistent with this observation, BLP-stimulated Tregs regained their inhibitory activity and prevented spontaneous colitis induced by effectors in severe combined immunodeficient mice. Our results demonstrate a previously unrecognized pathway by which TLR expressed on T cells may directly modulate the immune response. Thus, during an acute bacterial infection, BLP may rapidly increase the host's adaptive immunity by expanding effectors and also by attenuating the suppressive activity of Tregs. In the process, BLP also expands the Tregs, which recover their suppressive activity when the infection has subsided, in time to limit potential autoimmunity that might result from the overactivated effectors.
Toll样受体（TLRs）是先天性和适应性免疫系统的主要传感器，在抵御病原体结构保守成分的反应中起关键作用。合成细菌脂蛋白（BLP）Pam3Cys-SK4是一种TLR2激动剂，能够调节T细胞免疫反应。我们在此表明，在没有抗原呈递细胞的情况下，BLP与抗CD3抗体（T细胞受体（TcR）激活剂）一起诱导CD4+CD25+调节性T细胞（Tregs）和CD4+CD25-（效应）T细胞增殖。扩增的Tregs表现出短暂的抑制活性丧失。此外，BLP通过增加IL-2分泌使效应细胞对Tregs的抑制产生抗性。BLP还在T细胞受体激活后的最初8-15小时内短暂抑制Tregs中Foxp3（X连锁叉头/翼状螺旋转录因子）mRNA的诱导。与这一观察结果一致，BLP刺激的Tregs恢复了其抑制活性，并预防了严重联合免疫缺陷小鼠中效应细胞诱导的自发性结肠炎。我们的结果证明了一种以前未被认识的途径，通过该途径T细胞上表达的TLR可能直接调节免疫反应。因此，在急性细菌感染期间，BLP可能通过扩增效应细胞以及减弱Tregs的抑制活性来迅速增强宿主的适应性免疫力。在此过程中，BLP还扩增了Tregs，当感染消退时，Tregs恢复其抑制活性，及时限制可能由过度激活的效应细胞引起的潜在自身免疫。
