Systematic analysis of CDR contacts and pairing constraints between T cell receptor αβ chains

Area of Science:

• Immunology
• Structural Biology
• Bioinformatics

Background:

• T cell receptors (TCRs) mediate antigen specificity through complementarity determining regions (CDRs).
• Intra- and inter-chain CDR contacts within TCRs are crucial but less understood.
• Understanding TCR structure-function relationships is key to T cell immunity.

Purpose of the Study:

• To systematically analyze TCR crystallographic structures for conserved CDR contact patterns.
• To investigate sequence co-evolution and mutual information between TCRα and TCRβ chains.
• To explore the potential for predicting TCR pairing using sequence data.

Main Methods:

• Analysis of available TCR crystallographic structures.
• Identification of intra- and inter-chain CDR contacts.
• Mutual information analysis of TCRα and TCRβ sequences from antigen-specific sets.
• Development of sequence-based models for TCRα/TCRβ pairing prediction.

Main Results:

• Consistent patterns of intra- and inter-chain CDR contacts were identified in free and antigen-bound TCRs.
• TCRα and TCRβ chains recognizing shared antigens exhibit mutual information, indicating non-independence.
• Sequence-based models can partially predict TCRα/TCRβ pairing *de novo*.
• Conserved CDR contact patterns and sequence constraints are important for TCR structure and antigen recognition.

Conclusions:

• Intra- and inter-chain CDR contacts represent an under-appreciated aspect of TCR structure.
• Mutual sequence constraints between TCRα and TCRβ chains are linked to antigen specificity.
• These findings offer insights into T cell antigen recognition mechanisms and potential for predictive modeling.