Hahn Bevra H, Singh Ram Pyare, La Cava Antonio, Ebling Fanny M
Department of Medicine, Division of Rheumatology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
J Immunol. 2005 Dec 1;175(11):7728-37. doi: 10.4049/jimmunol.175.11.7728.
Lupus-prone (NZB x NZW)F1 mice spontaneously develop elevated titers of anti-DNA Abs that contain T cell determinants in their V(H) regions. We have previously shown that tolerization with an artificial peptide based on these T cell determinants (pConsensus (pCons)) can block production of anti-DNA Abs and prolong survival of the mice. In this study, we show that this protection depends in part on the generation of peripheral TGFbeta- and Foxp3-expressing inhibitory CD8+ (Ti) cells. These CD8+ Ti cells suppress anti-DNA IgG production both in vitro and in vivo and require up-regulated expression of both Foxp3 and TGFbeta to exert their suppressive function, as indicated by microarray analyses, small interfering RNA inhibition studies, and blocking experiments. Additionally, CD8+ Ti cells from pCons-tolerized mice were longer-lived suppressors that up-regulated expression of Bcl-2 and were more resistant to apoptosis than similar cells from naive mice. These data indicate that clinical suppression of autoimmunity after administration of pCons depends in part on the generation of CD8+ Ti cells that suppress secretion of anti-DNA Ig using mechanisms that include Foxp3, TGFbeta, and resistance to apoptosis.
易患狼疮的（NZB×NZW）F1小鼠会自发产生滴度升高的抗DNA抗体，这些抗体在其V(H)区域含有T细胞决定簇。我们之前已经表明，用基于这些T细胞决定簇的人工肽（pConsensus，pCons）进行耐受诱导可以阻断抗DNA抗体的产生并延长小鼠的生存期。在本研究中，我们表明这种保护作用部分依赖于外周表达转化生长因子β（TGFβ）和叉头框蛋白3（Foxp3）的抑制性CD8+（Ti）细胞的产生。这些CD8+ Ti细胞在体外和体内均能抑制抗DNA IgG的产生，并且如微阵列分析、小干扰RNA抑制研究和阻断实验所示，需要上调Foxp3和TGFβ的表达才能发挥其抑制功能。此外，来自pCons耐受小鼠的CD8+ Ti细胞是寿命更长的抑制细胞，其上调了Bcl-2的表达，并且比来自未免疫小鼠的类似细胞更抗凋亡。这些数据表明，给予pCons后对自身免疫的临床抑制部分依赖于CD8+ Ti细胞的产生，这些细胞利用包括Foxp3、TGFβ和抗凋亡在内的机制抑制抗DNA Ig的分泌。
