Andjelíc S, Khanna A, Suthanthiran M, Nikolić-Zugić J
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, USA.
J Immunol. 1997 Mar 15;158(6):2527-34.
Apoptosis plays an essential role in the development and homeostasis of the immune system. During lymphocyte development, potentially autoreactive cells are eliminated via the activation of a tightly regulated cell death program(s). Similar processes operate in mature lymphocytes, to control the magnitude of the normal immune response by eliminating activated lymphocytes. However, differences in susceptibility to signal-induced apoptosis between immature and mature lymphocytes are numerous. One well-characterized example occurs in response to Ca2+ elevation: peripheral T lymphocytes are resistant, while immature thymocytes are highly susceptible, to Ca2+-mediated cell death (CMCD). In this study, we show that the immunosuppressant cyclosporin A (CsA) primes splenic lymphocytes to undergo CMCD upon ionomycin stimulation. This CsA-induced CMCD affected both T and B lymphocytes. CsA-plug Ca2+-mediated apoptosis was dissected into a two-step process: first, CsA and Ca2+ synergized to induce TGF-beta 1 secretion by B cells; and then TGF-beta 1 and Ca2+ synergistically triggered T and B lymphocyte apoptosis. Together, our results suggest that lymphocyte apoptosis may play a role in CsA-induced immunosuppression via a TGF-beta-dependent mechanism.
细胞凋亡在免疫系统的发育和稳态中起着至关重要的作用。在淋巴细胞发育过程中，潜在的自身反应性细胞通过激活严格调控的细胞死亡程序而被清除。类似的过程也在成熟淋巴细胞中发挥作用，通过清除活化的淋巴细胞来控制正常免疫反应的强度。然而，未成熟和成熟淋巴细胞对信号诱导的细胞凋亡的敏感性存在许多差异。一个特征明确的例子是对钙离子升高的反应：外周T淋巴细胞具有抗性，而未成熟胸腺细胞对钙离子介导的细胞死亡（CMCD）高度敏感。在本研究中，我们表明免疫抑制剂环孢素A（CsA）使脾淋巴细胞在离子霉素刺激下易于发生CMCD。这种CsA诱导的CMCD影响T淋巴细胞和B淋巴细胞。CsA介导的钙离子凋亡被分解为两个步骤：首先，CsA和钙离子协同诱导B细胞分泌转化生长因子-β1（TGF-β1）；然后，TGF-β1和钙离子协同触发T淋巴细胞和B淋巴细胞凋亡。总之，我们的结果表明淋巴细胞凋亡可能通过依赖TGF-β的机制在CsA诱导的免疫抑制中发挥作用。
