Yu X Z, Zhu L, Davis J E, Tso J Y, Hansen J A, Anasetti C
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.
J Immunol. 1996 Oct 15;157(8):3420-9.
Peripheral T cell tolerance can be achieved through deletion of mature CD4+ cells activated by high dose Ag. We tested whether apoptosis of peripheral CD4+ cells could be induced by a stimulatory dose of Ag plus a soluble ligand to the nonpolymorphic epsilon-chain of the TCR-associated CD3 complex. CD4+ T cells from the DO10 mouse express a transgenic TCR-alphabeta specific for OVA peptide 323-339 presented by I-A(d). OVA alone induced clonal activation and expansion of peripheral CD4+/TCR transgene+ cells. Simultaneous exposure to specific Ag plus soluble anti-CD3 Fos, a nonmitogenic anti-CD3epsilon genetically engineered F(ab')2-like Ab, blocked expansion and induced death of CD4+/TCR transgene+ cells, but not CD4+/TCR transgene- T cells. In contrast, a mitogenic anti-CD3epsilon Ab induced polyclonal activation and nonselective T cell death. Sequential stimulation by Ag followed by anti-CD3 Fos also induced death of TCR transgene+ cells, whereas stimulation by anti-CD3 Fos followed by Ag did not affect cell viability or function. Anti-CD3 Fos-induced death was associated with DNA fragmentation characteristic of apoptosis, was facilitated by IL-2, and was initiated by stimulation during the S-G2 phases of the cell cycle. Anti-CD3 Fos could induce deletion of Ag-activated T cells by apoptosis in vivo. Thus, a soluble, non-Fc-binding anti-CD3 Ab can induce programmed cell death of Ag-activated peripheral CD4+ T cells by CD3epsilon cross-linking during S or G2. Peripheral T cell deletion by activation-driven apoptosis is under cell cycle control and can be exploited to achieve selective immunosuppression by nonmitogenic anti-CD3epsilon Abs.
外周T细胞耐受性可通过清除被高剂量抗原激活的成熟CD4⁺细胞来实现。我们测试了是否可以通过刺激剂量的抗原加上TCR相关CD3复合物非多态性ε链的可溶性配体来诱导外周CD4⁺细胞凋亡。来自DO10小鼠的CD4⁺T细胞表达对由I-A(d)呈递的OVA肽323-339具有特异性的转基因TCR-αβ。单独的OVA诱导外周CD4⁺/TCR转基因⁺细胞的克隆激活和扩增。同时暴露于特异性抗原加上可溶性抗CD3 Fos（一种非促有丝分裂的抗CD3ε基因工程F(ab')₂样抗体）可阻断CD4⁺/TCR转基因⁺细胞的扩增并诱导其死亡，但对CD4⁺/TCR转基因⁻T细胞无影响。相比之下，促有丝分裂的抗CD3ε抗体诱导多克隆激活和非选择性T细胞死亡。先由抗原刺激然后再用抗CD3 Fos刺激也可诱导TCR转基因⁺细胞死亡，而先由抗CD3 Fos刺激然后再用抗原刺激则不影响细胞活力或功能。抗CD3 Fos诱导的死亡与凋亡特有的DNA片段化有关，IL-2可促进这种死亡，并且是由细胞周期S-G₂期的刺激引发的。抗CD3 Fos可在体内通过凋亡诱导抗原激活的T细胞缺失。因此，一种可溶性、不结合Fc的抗CD3抗体可通过在S期或G₂期交联CD3ε来诱导抗原激活的外周CD4⁺T细胞发生程序性细胞死亡。通过激活驱动的凋亡进行外周T细胞缺失受细胞周期控制，并且可被利用来通过非促有丝分裂的抗CD3ε抗体实现选择性免疫抑制。
