2022-08-18 フランクフルト大学
膜結合型T細胞受容体と抗原の複合体の構造を可視化することに初めて成功した。低温電子顕微鏡でとらえた抗原結合構造と抗原のない受容体の構造を比較することで、活性化機構を解明する最初の手がかりを得ることができた。
研究チームは、メラノーマの免疫療法に用いられるT細胞受容体の中から、抗原とできるだけ強固に結合するように何段階にもわたって最適化されたものを選び、構造解析に取り組んだ。
構造解析に基づいて、T細胞レセプターがどのように抗原を認識し、どのように抗原結合後のシグナル伝達が行われるかを明らかにすることができた。
<関連情報>
- https://aktuelles.uni-frankfurt.de/englisch/immune-system-first-image-of-antigen-bound-t-cell-receptor-at-atomic-resolution/
- https://www.cell.com/cell/fulltext/S0092-8674(22)00913-8
pMHCでリガリングされた腫瘍特異的T細胞受容体の完全な組み立て構造 Structure of a fully assembled tumor-specific T cell receptor ligated by pMHC
Lukas Sušac ,Mai T. Vuong ,Christoph Thomas,Sören von Bülow,Caitlin O’Brien-Ball,Ana Mafalda Santos,Ricardo A. Fernandes,Gerhard Hummer,Robert Tamp,Simon J. Davis
Cell August 18, 2022
DOI:https://doi.org/10.1016/j.cell.2022.07.010
Highlights
•Connecting peptides create rigid links to stabilize membrane-bound TCR subunits
•Sterol lipid contributes to transmembrane assembly of the TCR complex
•A pMHC/TCR structure highlights the cooperative nature of antigen recognition
•TCR signaling may be triggered without spontaneous structural rearrangements
Summary
The T cell receptor (TCR) expressed by T lymphocytes initiates protective immune responses to pathogens and tumors. To explore the structural basis of how TCR signaling is initiated when the receptor binds to peptide-loaded major histocompatibility complex (pMHC) molecules, we used cryogenic electron microscopy to determine the structure of a tumor-reactive TCRαβ/CD3δγε2ζ2 complex bound to a melanoma-specific human class I pMHC at 3.08 Å resolution. The antigen-bound complex comprises 11 subunits stabilized by multivalent interactions across three structural layers, with clustered membrane-proximal cystines stabilizing the CD3-εδ and CD3-εγ heterodimers. Extra density sandwiched between transmembrane helices reveals the involvement of sterol lipids in TCR assembly. The geometry of the pMHC/TCR complex suggests that efficient TCR scanning of pMHC requires accurate pre-positioning of T cell and antigen-presenting cell membranes. Comparisons of the ligand-bound and unliganded receptors, along with molecular dynamics simulations, indicate that TCRs can be triggered in the absence of spontaneous structural rearrangements.
