Institute for Bioscience and Biotechnology Research, University of Maryland, WM Keck Laboratory for Structural Biology, Rockville, MD, USA.
EMBO J. 2011 Mar 16;30(6):1137-48. doi: 10.1038/emboj.2011.21. Epub 2011 Feb 4.
The failure to eliminate self-reactive T cells during negative selection is a prerequisite for autoimmunity. To escape deletion, autoreactive T-cell receptors (TCRs) may form unstable complexes with self-peptide-MHC by adopting suboptimal binding topologies compared with anti-microbial TCRs. Alternatively, escape can occur by weak binding between self-peptides and MHC. We determined the structure of a human autoimmune TCR (MS2-3C8) bound to a self-peptide from myelin basic protein (MBP) and the multiple sclerosis-associated MHC molecule HLA-DR4. MBP is loosely accommodated in the HLA-DR4-binding groove, accounting for its low affinity. Conversely, MS2-3C8 binds MBP-DR4 as tightly as the most avid anti-microbial TCRs. MS2-3C8 engages self-antigen via a docking mode that resembles the optimal topology of anti-foreign TCRs, but is distinct from that of other autoreactive TCRs. Combined with a unique CDR3β conformation, this docking mode compensates for the weak binding of MBP to HLA-DR4 by maximizing interactions between MS2-3C8 and MBP. Thus, the MS2-3C8-MBP-DR4 complex reveals the basis for an alternative strategy whereby autoreactive T cells escape negative selection, yet retain the ability to initiate autoimmunity.
自身反应性 T 细胞在阴性选择过程中未能被清除是自身免疫的前提条件。为了逃避删除，自身反应性 T 细胞受体 (TCR) 可能通过采用与抗微生物 TCR 相比不太理想的结合拓扑结构，与自身肽-MHC 形成不稳定的复合物。或者，通过自身肽和 MHC 之间的弱结合来实现逃逸。我们确定了与来自髓鞘碱性蛋白 (MBP)和多发性硬化症相关的 MHC 分子 HLA-DR4 的自身肽结合的人类自身免疫 TCR (MS2-3C8) 的结构。MBP 松散地容纳在 HLA-DR4 结合槽中，这解释了其低亲和力。相反，MS2-3C8 与 MBP-DR4 的结合与最贪婪的抗微生物 TCR 一样紧密。MS2-3C8 通过类似于抗外源 TCR 的最佳拓扑结构的对接模式与自身抗原结合，但与其他自身反应性 TCR 不同。这种对接模式与独特的 CDR3β 构象相结合，通过最大化 MS2-3C8 与 MBP 之间的相互作用，弥补了 MBP 与 HLA-DR4 的弱结合。因此，MS2-3C8-MBP-DR4 复合物揭示了自身反应性 T 细胞逃避阴性选择但保留引发自身免疫能力的替代策略的基础。
