Abramson Family Cancer Research Institute, Division of Infectious Diseases, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Immunol. 2010 Dec 15;185(12):7151-5. doi: 10.4049/jimmunol.1003193. Epub 2010 Nov 12.
A hallmark of autoimmune lymphoproliferative syndrome (ALPS), caused by mutation of the Fas death receptor, is massive lymphadenopathy from aberrant expansion of CD4(-)CD8(-) (double-negative [DN]) T cells. Eomesodermin (Eomes) is a member of the T-box family of transcription factors and plays critical roles in effector cell function and memory cell fitness of CD8(+) T lymphocytes. We provide evidence in this study that DN T cells exhibit dysregulated expression of Eomes in humans and mice with ALPS. We also find that T cell-specific deletion of Eomes prevents lymphoid hypertrophy and accumulation of DN T cells in Fas-mutant mice. Although Eomes has critical physiological roles in the function and homeostasis of CD8(+) T cells, overexpression of Eomes appears to enable pathological induction or expansion of unusual CD8-related T cell subsets. Thus, antagonism of Eomes emerges as a therapeutic target for DN T cell ablation in ALPS.
自身免疫性淋巴增生综合征 (ALPS) 的一个特征是 Fas 死亡受体的突变，导致 CD4(-)CD8(-)（双阴性 [DN]）T 细胞异常扩增，从而导致淋巴结病。Eomesodermin (Eomes) 是 T 盒家族转录因子的成员，在 CD8(+)T 淋巴细胞的效应细胞功能和记忆细胞适应性中发挥关键作用。本研究提供了证据表明，在具有 ALPS 的人类和小鼠中，DN T 细胞表现出 Eomes 的失调表达。我们还发现，Eomes 的 T 细胞特异性缺失可防止 Fas 突变小鼠的淋巴样肥大和 DN T 细胞的积累。尽管 Eomes 在 CD8(+)T 细胞的功能和体内平衡中具有重要的生理作用，但 Eomes 的过表达似乎能够诱导或扩大异常的 CD8 相关 T 细胞亚群。因此，拮抗 Eomes 成为 ALPS 中 DN T 细胞消融的治疗靶点。
