Recognition mechanism of non-peptide antigens by human γδ T cells

Abstract

The majority of γδ T cells in adult human blood exhibit Vγ2/Vδ2-TCR and specifically respond to various kinds of non-peptide antigens. In this study, we comparatively analyzed the CDR3 repertoires of Vγ2-γ and Vδ2-δ chain genes in the adult and cord blood. It was confirmed that the vast majority of adult γδ T cells exhibited Vγ2-γ chains bearing a Jγ1.2 segment with no or short N-region and Vδ2-δ chains with a conserved hydrophobic residue (leucine, valine or isoleucine) at position 97 encoded by N-region of Vδ/Jδ junction (δL97). The cord blood cells stimulated with pyrophosphomonoester antigen in vitro showed preferential expansion of the γδ T cells expressing Vγ2- and Vδ2-TCR chains with these structural features as compared with those stimulated with a polyclonal mitogen phytohemagglutinin. TCR gene transfer studies indicated that alanine substitution of lysine at position 108 in Jγ1.2 (γK108) or δL97 abrogated the responsiveness of Vγ2/Vδ2-TCR to all kinds of the non-peptide antigens without affecting the response to anti-CD3 antibody. Furthermore, alanine substitution of arginine at position 51 in Vδ2 segment (δR51 adjacent to γK108 in the Vγ2/Vδ2-γδ TCR also abolished the antigen responsiveness. These results strongly suggested that a hydrophobic and two cationic residues (δL97, γK108 and δR51) clustered in a particular topology at the surface edge of the pocket structure of Vγ2/Vδ2-γδ TCR played essential roles in the recognition of non-peptide antigens.