一些细胞毒性机制被认为是T细胞参与1型糖尿病患者β细胞死亡的重要原因。然而，在体内环境和体外环境下β细胞对这些机制的敏感性很有可能是不同的。CD4(+) T细胞和CD8(+) T细胞对于1型糖尿病的发展十分重要，CD4(+) T细胞和CD8(+) T细胞有可能通过独立的机制导致β细胞死亡，这一机制可能涉及第三类细胞毒性细胞的激活。我们将致糖尿病性的转基因T细胞转染到正常受体、突变受体以及骨髓嵌合体受体小鼠体内，用以研究导致β细胞死亡的主要细胞毒性机制在β细胞死亡过程中所起的作用。我们发现：1）由于CD4（+）T细胞不能直接作用于人MHCII类分子阴性的β细胞。CD4（+）T细胞杀伤β细胞需要通过由肿瘤坏死因子-α（TNF-α）介导的自身细胞毒性细胞受体的激活实现，这一过程独立于Fas配体或穿孔素，但CD4（+）T细胞产生的TNF-α对β细胞没有直接的细胞毒性作用，而仅作为诱导第三类细胞细胞毒性的诱导剂发挥作用。2）CD8(+) T细胞破坏β细胞的细胞毒性机制受限于穿孔素和Fas配体，这些分子的双重敲除可以消除T细胞的致糖尿病的能力。穿孔素，Fas配体和TNF-α组成最小效应细胞因子通路组通过胰岛素特异性CD8+T细胞激活诱导糖尿病。而且3）个体的CD8(+) T细胞克隆通过一个尚未明确的机制来选择它们的细胞毒性武器并且通过不依赖Fas途径及Fas依赖性（~40%的克隆）途径损伤它们的靶点。TNF-α可协助Fas依赖性途径的损伤。总之，Fas和穿孔素都十分重要，它们本身可以杀伤β细胞，Fas配体和穿孔素介导的两类机制是CD8+T细胞的细胞毒性机制中必不可少的，其他机制可参与但仅是协助的作用。同时我们的结果表明在体内Fas配体调节的β细胞损伤需要TNF-α调节的信号通路的协同作用，而T细胞的长期激活需要包括杀伤机制在内的不同生理特性来共同实现。

Cytotoxic Mechanisms Employed by Mouse T Cells to Destroy Pancreatic β-Cells
Several cytotoxic mechanisms have been attributed to T cells participating in β-cell death in type 1 diabetes. However, sensitivity of β-cells to these mechanisms in vitro and in vivo is likely to be different. Moreover, CD4(+) and CD8(+) T cells may use distinct mechanisms to cause β-cell demise that possibly involve activation of third-party cytotoxic cells. We used the transfer of genetically modified diabetogenic T cells into normal, mutant, and bone marrow chimeric recipients to test the contribution of major cytotoxic mechanisms in β-cell death. We found that: 1) the killing of β-cells by CD4(+) T cells required activation of the recipient's own cytotoxic cells via tumor necrosis factor-α (TNF-α); 2) CD8(+) T-cell cytotoxic mechanisms destroying β-cells were limited to perforin and Fas ligand, as double knockouts of these molecules abrogated the ability of T cells to cause diabetes; and 3) individual CD8(+) T-cell clones chose their cytotoxic weaponry by a yet unknown mechanism and destroyed their targets via either Fas-independent or Fas-dependent (∼40% of clones) pathways. Fas-dependent destruction was assisted by TNF-α.