Zheng Jian, Liu Yinping, Qin Gang, Chan Ping-Lung, Mao Huawei, Lam Kwok-Tai, Lewis David B, Lau Yu-Lung, Tu Wenwei
Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, People's Republic of China.
J Immunol. 2009 Sep 15;183(6):3742-50. doi: 10.4049/jimmunol.0901329. Epub 2009 Aug 14.
Although recent studies have focused on CD4(+) regulatory T cells (Treg), CD8(+) Treg have also been reported to play important roles in the induction and maintenance of immune tolerance. Adoptive transfer of CD8(+) Treg in rodents or induction of CD8(+) Treg in humans can prevent or treat allograft rejection and autoimmune diseases. However, no approaches have been reported for the generation of human Ag-specific CD8(+) Treg at a practical scale for clinical use. Here, we found that two novel CD8(+) T cell subsets with different levels of CD8 surface expression, CD8(high) and CD8(low), could be induced from naive CD8(+) precursors in vitro by allogeneic CD40-activated B cells, whereas only CD8(high) T cells were alloantigen-specific Treg with relatively poor alloantigen-specific cytotoxicity. Importantly, alloantigen-specific CD8(high) Treg could be induced and expanded from naive CD8(+)CD25(-) T cells at a large scale after 3 wk of culture without exogenous cytokines. These induced alloantigen-specific Treg were CD45RO(+) and CCR7(-) memory cells, and they expressed Foxp3, CD25, CD27, CD28, and CD62L. The induction and expansion of CD8(high) Treg by CD40-activated B cells were dependent on endogenously expressed IFN-gamma, IL-2, IL-4, and CTLA-4. This approach may facilitate the clinical application of CD8(+) Treg-based immunotherapy in transplantation and autoimmune diseases.
尽管近期的研究聚焦于CD4(+)调节性T细胞（Treg），但也有报道称CD8(+)Treg在免疫耐受的诱导和维持中发挥重要作用。在啮齿动物中过继转移CD8(+)Treg或在人类中诱导CD8(+)Treg可预防或治疗同种异体移植排斥反应和自身免疫性疾病。然而，尚未有报道称存在可大规模生成用于临床的人抗原特异性CD8(+)Treg的方法。在此，我们发现两种具有不同CD8表面表达水平的新型CD8(+)T细胞亚群，即CD8(高)和CD8(低)，可在体外由同种异体CD40激活的B细胞从初始CD8(+)前体细胞诱导产生，而只有CD8(高)T细胞是同种异体抗原特异性Treg，其同种异体抗原特异性细胞毒性相对较弱。重要的是，在无外源性细胞因子的情况下培养3周后，可从初始CD8(+)CD25(-)T细胞大规模诱导并扩增同种异体抗原特异性CD8(高)Treg。这些诱导产生的同种异体抗原特异性Treg是CD45RO(+)和CCR7(-)记忆细胞，并且它们表达Foxp3、CD25、CD27、CD28和CD62L。CD40激活的B细胞对CD8(高)Treg的诱导和扩增依赖于内源性表达的IFN-γ、IL-2、IL-4和CTLA-4。这种方法可能会促进基于CD8(+)Treg的免疫疗法在移植和自身免疫性疾病中的临床应用。
