Su Y, Jevnikar A M, Huang X, Lian D, Zhang Z -X
Am J Transplant. 2014 Mar;14(3):580-93. doi: 10.1111/ajt.12614.
Memory T (Tm) cells pose a major barrier to long-term transplant survival. Whether regulatory T cells (Tregs)can control them remains poorly defined. Previously,we established that double-negative (DN) Tregs suppress effector T (Teff) cells. Here, we demonstrate that DNTregs effectively suppress CD4+/CD8+Teff and CD8+Tm but not CD4+Tm cells, whereas the suppression on CD8+Tm is abrogated by perforin (PFN) deficiency in DNTregs. Consistently, in a BALB/c to B6-Rag1-/-skin transplantation, transfer of DN Tregs suppressed the rejection mediated by CD4þ/CD8+Teff and CD8+Tmcells (76.0±4.9, 87.5±5.0 and 63.0±4.7 days, respectively)but not CD4þTmcells (25.3±1.4 days). Both CD8þ effector memory T and central memory T compartments significantly reduced after DN Treg transfer. CD4+Tm highly expresses granzyme B (GzmB) inhibitor serine protease inhibitor-6 (Spi6). Spi6 deficiency renders CD4þTm susceptible to DN Treg suppression. In addition,transfer of WT DN Tregs, but not PFN-/-DN Tregs,inhibited the skin allograft rejection mediated by Spi6-/-CD4þTm(75.5±7.9 days). In conclusion, CD4+ and CD8+Tm cells differentially respond toDNTregs’ suppression.The GzmB resistance conferred by Spi6 in CD4þTm cells might hint at the physiological significance of Tmpersistence
记忆性T（Tm）细胞是长期移植存活的主要障碍。调节性T细胞（Tregs）能否控制它们仍不清楚。此前，我们发现双阴性（DN）Tregs可抑制效应性T（Teff）细胞。在此，我们证明DN Tregs能有效抑制CD4+/CD8+Teff和CD8+Tm细胞，但不能抑制CD4+Tm细胞，而DN Tregs中穿孔素（PFN）缺陷可消除对CD8+Tm细胞的抑制作用。同样，在BALB/c到B6-Rag1-/-皮肤移植中，DN Tregs的转移抑制了由CD4þ/CD8+Teff和CD8+Tm细胞介导的排斥反应（分别为76.0±4.9、87.5±5.0和63.0±4.7天），但不能抑制CD4þTm细胞介导的排斥反应（25.3±1.4天）。DN Tregs转移后，CD8þ效应性记忆T细胞和中枢记忆T细胞亚群均显著减少。CD4+Tm细胞高表达颗粒酶B（GzmB）抑制剂丝氨酸蛋白酶抑制剂-6（Spi6）。Spi6缺陷使CD4þTm细胞易受DN Tregs抑制。此外，野生型DN Tregs而非PFN-/-DN Tregs的转移抑制了由Spi6-/-CD4þTm细胞介导的皮肤同种异体移植排斥反应（75.5±7.9天）。总之，CD4+和CD8+Tm细胞对DN Tregs的抑制反应不同。Spi6赋予CD4þTm细胞的GzmB抗性可能暗示了Tm细胞持续存在的生理意义
