T cell receptor variable β20-1 harbors a nucleotide binding pocket in the CDR2β loop

Area of Science:

• Immunology
• Molecular Biology
• Computational Biology

Background:

• T cells expressing T cell receptor Vβ20-1 (TCRVβ20-1) exhibit unique properties.
• TCRs can bind small molecules independently of the peptide-MHC class II (pMHC-II) complex.
• The specific natural ligands for TCRVβ20-1 remain largely unidentified.

Purpose of the Study:

• To identify natural ligands that bind to a specific pocket on the CDR2β loop of TCRVβ20-1.
• To investigate the functional consequences of this ligand-TCR interaction.
• To explore the role of nucleotides as potential ligands for TCRVβ20-1.

Main Methods:

• Molecular docking simulations to predict ligand binding.
• Identification of Guanine and Adenine di- and tri-nucleotides as potential binders.
• Molecular dynamic simulations and computational solubility tests for validation.
• T cell proliferation assays using CD4/Vβ20-1+ T cells and other T cell isolates.

Main Results:

• Guanine and Adenine di- and tri-nucleotides were identified as ligands binding to the CDR2β loop pocket of TCRVβ20-1.
• This nucleotide-binding interaction is novel compared to other known TCR small molecule binding sites.
• Molecular simulations confirmed the plausibility and stability of these binding interactions.
• Nucleotides induced T cell proliferation in CD4/Vβ20-1+ T cells but not in other T cell populations.

Conclusions:

• Nucleotides, specifically Guanine and Adenine derivatives, act as natural ligands for TCRVβ20-1.
• This interaction represents a novel mechanism of T cell activation independent of the pMHC-II pathway.
• The findings establish a functional role for nucleotides in T cells expressing the TCRVβ20-1 subtype.
• This research merges computational and experimental approaches to uncover new aspects of T cell receptor function.