Evolutionarily conserved features contribute to αβ T cell receptor specificity.

Area of Science:

• Immunology
• Evolutionary Biology
• Molecular Biology

Background:

• Alpha-beta T cell receptors (TCRs) recognize foreign antigens presented by major histocompatibility complex (MHC) proteins.
• Evidence suggests coevolution between TCRs and MHC molecules due to conserved features in germline-encoded TCR segments.
• The evolutionary conservation of TCR specificity for MHC molecules requires direct assessment.

Purpose of the Study:

• To directly assess the evolutionary conservation of alpha-beta TCR specificity for MHC and MHC-like molecules.
• To investigate the role of specific amino acid residues in TCR-MHC binding across different vertebrate species.

Main Methods:

• Sequence comparisons of TCR Vβ segments from various jawed vertebrates.
• Construction and functional testing of chimeric TCRs incorporating Vβ segments from amphibians, bony fish, and cartilaginous fish.
• Assessment of chimeric TCR recognition of antigens presented by mouse MHC class II and CD1d.

Main Results:

• Sequence analysis revealed shared amino acids in complementarity determining region 2 (CDR2) of Vβ segments from distantly related vertebrates.
• Chimeric TCRs engineered with Vβs from diverse fish and amphibians demonstrated recognition of mouse MHC class II and CD1d.
• This recognition was critically dependent on the conserved CDR2 amino acid residues.

Conclusions:

• Key features of TCRs governing specificity for MHC and MHC-like molecules were selected early in vertebrate evolution.
• These specificity determinants have been maintained across species separated by over 400 million years of evolution.
• The findings highlight a deep evolutionary conservation in the fundamental mechanisms of adaptive immunity.