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Updated: Oct 19, 2025
16:10
A TIRF Microscopy Technique for Real-time, Simultaneous Imaging of the TCR and its Associated Signaling Proteins
Published on: March 22, 2012
24.1K
Atypical TNF-TNFR superfamily binding interface in the GITR-GITRL complex for T cell activation
Min Zhao1, Lijun Fu2, Yan Chai3
1Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
Cell Reports
|September 22, 2021
Summary
Researchers elucidated the structure of mouse GITR and its ligand, revealing a unique binding mechanism distinct from typical TNF superfamily interactions. This finding advances understanding of immune regulation and biologic drug design targeting GITR/GITRL.
Area of Science:
- Immunology
- Structural Biology
- Biochemistry
Background:
- Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is a key regulator of T cell immune responses.
- Understanding the molecular interactions of GITR and its ligand (GITRL) is crucial for immune modulation.
Purpose of the Study:
- To determine the complex structure of mouse GITR (mGITR) and mGITRL.
- To compare the binding interface of mGITR/mGITRL with other tumor necrosis factor superfamily (TNFSF)/TNF receptor superfamily (TNFRSF) members.
- To investigate the conservation and functional implications of the GITR/GITRL binding interface across species.
Main Methods:
- X-ray crystallography to determine the complex structure of mGITR and mGITRL.
- Biochemical assays and mutational analysis to identify key interacting residues.
- Cross-species binding and signaling assays.
Main Results:
- The binding interface of mGITR and mGITRL is distinct from canonical TNFSF/TNFRSF interactions.
- mGITR binds its ligand via a single domain, with the mGITRL interface located distally from conserved sites.
- The GITR/GITRL binding interface is conserved between mouse and human, and specific mutations enable cross-species recognition and signaling.
Conclusions:
- The unique structural and binding characteristics of the GITR/GITRL complex expand the known diversity of TNFSF/TNFRSF interactions.
- Understanding these interactions provides a foundation for designing targeted biologics for immune system modulation.
- The identified cross-species conserved residues offer opportunities for developing novel immunotherapeutic agents.
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