Evolutionary conservation of major histocompatibility complex-DR/peptide/T cell interactions in primates

Area of Science:

• Immunogenetics
• Evolutionary Biology
• Molecular Immunology

Background:

• Major histocompatibility complex (MHC) polymorphisms often predate species divergence.
• The Mhc-DRB1*03 allelic lineage is found in humans, chimpanzees, and rhesus macaques, indicating its presence in a common ancestor ~30 million years ago.

Purpose of the Study:

• To investigate the biological significance of conserved and varied sequences within the trans-species Mhc-DRB1*03 lineage.
• To examine the antigen-binding and presentation capabilities of different Mhc-DRB1*03 lineage members.

Main Methods:

• Studied the binding of Mycobacterium leprae and M. tuberculosis hsp65 p3-13 peptide to various primate Mhc-DRB1*03 molecules.
• Compared amino acid sequences in the antigen-binding sites of human, chimpanzee, and rhesus macaque Mhc-DRB1*03 alleles.
• Assessed the ability of nonhuman primate antigen-presenting cells to activate human T cells.

Main Results:

• The hsp65 p3-13 peptide binds to human HLA-DR17(3) and also to Mhc-DRB1*03 molecules from chimpanzees and rhesus macaques.
• Specific amino acid residues at positions 9-13 and 26-31 in the antigen-binding site are critical for p3-13 binding and are uniquely shared across these species.
• Nonhuman primate antigen-presenting cells binding p3-13 can activate HLA-DR17-restricted T cells, despite some sequence variations in Mhc-DRB1*03 lineage members.

Conclusions:

• Certain amino acid motifs within the MHC class II antigen-binding site crucial for peptide binding and T cell receptor recognition have been conserved for over 30 million years.
• This ancient conservation highlights the evolutionary importance of specific MHC residues in immune response across primate species.