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- Title
Structural and functional insights into the modulation of T cell costimulation by monkeypox virus protein M2.
- Authors
Yang, Shangyu; Wang, Yong; Yu, Feiyang; Cheng, Rao; Zhang, Yiwei; Zhou, Dan; Ren, Xuanxiu; Deng, Zengqin; Zhao, Haiyan
- Abstract
The rapid spread of monkeypox in multiple countries has resulted in a global public health threat and has caused international concerns since May 2022. Poxvirus encoded M2 protein is a member of the poxvirus immune evasion family and plays roles in host immunomodulation via the regulation of innate immune response mediated by the NF-κB pathway and adaptive immune response mediated by B7 ligands. However, the interaction of monkeypox virus (MPXV) M2 with B7 ligands and structural insight into poxviral M2 function have remained elusive. Here we reveal that MPXV M2, co-existing as a hexamer and a heptamer, recognizes human B7.1 and B7.2 (hB7.1/2) with high avidities. The binding of oligomeric MPXV M2 interrupts the interactions of hB7.1/2 with CD28 and CTLA4 and subverts T cell activation mediated by B7.1/2 costimulatory signals. Cryo-EM structures of M2 in complex with hB7.1/2 show that M2 binds to the shallow concave face of hB7.1/2 and displays sterically competition with CD28 and CTLA4 for the binding to hB7.1/2. Our findings provide structural mechanisms of poxviral M2 function and immune evasion deployed by poxviruses. The B7 family proteins B7.1 (CD80) and B7.2 (CD86) are two well-studied costimulatory ligands that play critical roles in host T cell immunity against viral infection. In this study, the authors show that oligomeric M2 protein encoded by monkeypox virus serves as a viral decoy receptor and inhibits T cell activation mediated by hB7.1/2 co-stimulation via the blockade of CD28 binding to human B7.1/2, providing molecular mechanisms of poxvirus M2 function and immune evasion.
- Subjects
VIRAL proteins; MONKEYPOX; T cells; IMMUNOREGULATION; T cell receptors; VIRUS diseases; CD28 antigen
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40748-2