Centre for Kidney Research, Children's Hospital at Westmead, Westmead, Sydney, NSW 2145, Australia.
J Am Soc Nephrol. 2012 Jun;23(6):1058-67. doi: 10.1681/ASN.2011090914. Epub 2012 Apr 5.
Autoreactive T cells play a pivotal role in the pathogenesis of autoimmune kidney disease. T cell vaccination (TCV) may limit autoimmune disease and induce CD8+ regulatory T cells (Tregs). We used Heymann nephritis (HN), a rat model of human membranous nephritis, to study the effects of TCV on autoimmune kidney disease. We harvested CD4+ T cells from renal tubular antigen (Fx1A) -immunized rats and activated these cells in vitro to express the MHC Class Ib molecule Qa-1. Vaccination of Lewis rats with these autoreactive Fx1A-induced T cells protected against HN, whereas control-primed T cells did not. Rats that underwent TCV had lower levels of proteinuria and serum creatinine and significantly less glomerulosclerosis, tubular damage, and interstitial infiltrates. Furthermore, these rats expressed less IFN-γ and IL-6 in splenocytes, whereas the numbers of Tregs and the expression of Foxp3 were unchanged. In vitro cytotoxicity assays showed CD8+ T cell-mediated elimination of Qa-1-expressing CD4+ T cells. In vivo, TCV abrogated the increase in Qa-1-expressing CXCR5+ TFH cells observed in HN compared with controls. Taken together, these results suggest that TCV protects against autoimmune kidney disease by targeting Qa-1-expressing autoreactive CD4+ cells.
自身反应性 T 细胞在自身免疫性肾病的发病机制中起着关键作用。T 细胞疫苗接种 (TCV) 可能限制自身免疫性疾病并诱导 CD8+调节性 T 细胞 (Treg)。我们使用 Heymann 肾炎 (HN)，一种人类膜性肾炎的大鼠模型，研究了 TCV 对自身免疫性肾病的影响。我们从肾管状抗原 (Fx1A) 免疫大鼠中提取 CD4+T 细胞，并在体外激活这些细胞以表达 MHC Class Ib 分子 Qa-1。用这些自身反应性 Fx1A 诱导的 T 细胞对 Lewis 大鼠进行疫苗接种可预防 HN，而对照引发的 T 细胞则不能。接受 TCV 的大鼠蛋白尿和血清肌酐水平较低，肾小球硬化、肾小管损伤和间质浸润明显减少。此外，这些大鼠脾细胞中 IFN-γ 和 IL-6 的表达水平降低，而 Treg 的数量和 Foxp3 的表达水平不变。体外细胞毒性测定显示 CD8+T 细胞介导消除表达 Qa-1 的 CD4+T 细胞。在体内，与对照组相比，TCV 消除了 HN 中观察到的表达 Qa-1 的 CXCR5+TFH 细胞的增加。综上所述，这些结果表明 TCV 通过靶向表达 Qa-1 的自身反应性 CD4+细胞来保护免受自身免疫性肾病的侵害。
