Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
J Immunol. 2009 Dec 15;183(12):7761-7. doi: 10.4049/jimmunol.0902181.
T cell education in the thymus is critical for establishing a functional, yet self-tolerant, T cell repertoire. Negative selection is a key process in enforcing self-tolerance. There are many questions that surround the mechanism of negative selection, but it is currently held that apoptosis initiated by Bim and/or Nur77 is critical for negative selection. Recent studies, however, have questioned the necessity of Bim in maintaining both central and peripheral T cell tolerance. To reconcile these apparently contradictory findings, we examined the role of Bim in negative selection in the well-characterized, physiological HY(cd4) mouse model. We found that while Bim expression was required for CD4(+)CD8(+) double-positive thymocyte apoptosis, it was not required for negative selection. Furthermore, Bim deficiency did not alter the frequency or affinity of male reactive cells that escape negative selection in an oligoclonal repertoire. Collectively, these studies indicate that negative selection occurs efficiently in the absence of apoptosis and suggest that the current paradigm of negative selection requiring apoptosis be revisited.
胸腺中的 T 细胞发育对于建立功能性但自身耐受的 T 细胞库至关重要。负选择是实施自身耐受的关键过程。围绕负选择的机制存在许多问题，但目前认为由 Bim 和/或 Nur77 引发的细胞凋亡对于负选择至关重要。然而，最近的研究对 Bim 在维持中枢和外周 T 细胞耐受中的必要性提出了质疑。为了解决这些明显矛盾的发现，我们在特征明确的生理性 HY(cd4)小鼠模型中研究了 Bim 在负选择中的作用。我们发现，虽然 Bim 表达对于 CD4(+)CD8(+)双阳性胸腺细胞凋亡是必需的，但对于负选择不是必需的。此外，Bim 缺陷不会改变在寡克隆库中逃避负选择的雄性反应性细胞的频率或亲和力。总之，这些研究表明，在没有细胞凋亡的情况下，负选择仍能有效发生，并提示需要重新审视当前的细胞凋亡需要负选择的范例。
