Antigen Recognition by γδ T‐cells
Unlike αβ T‐cells, γδ T‐cells recognize antigens directly without a requirement for antigen processing. Human γδ T‐cells have been isolated that directly recognize the MHC‐related molecules MICA or MICA, or recognize CD1c irrespective of any lipid or glycolipid antigen; anlarly in mice γδ T‐cells are present that recognize the MHC class I molecule I‐Ek (irrespective of which peptide is bound) or the MHC‐like non‐peptide‐binding molecules T10 and T22. Other γδ T‐cells can respond to infectious agents such as cytomegalovirus. It would appear that γδ cells have a distinctive role complementary to that of the αβ population and function in the direct recognition of microbial pathogens and of damaged or stressed host cells.
Evidence for direct recognition of antigen by γδ T‐cells came from experiments such as those involving a γδ T‐cell clone specific for the herpes simplex virus glycoprotein‐1. This clone could be stimulated by the native protein bound to plastic, suggesting that the cells are triggered by cross‐linking of their receptors by antigen that they recognize in the intact native state just as antibodies do. There are structural arguments to give weight to this view. Notwithstanding the inclusion of a short D segment in the β chain, the CDR3 loops are comparable in length and relatively constrained with respect to size in the α and β chains of the αβ TCR, reflecting a relative constancy in the size of the MHC–peptide complexes to which they bind. CDR3 regions in the immunoglobulin light chains are short and similarly constrained in length, but in the heavy chains they are longer and more variable in length, related to their need to recognize a wide range of epitopes. Quite strikingly, the γδ TCRs resemble antibodies in that the γ chain CDR3 loops are short with a narrow length distribution, while in the δ chain they are relatively long with a broad length distribution. Therefore, in this respect, the γδ TCR resembles antibody more than the αβ TCR. When the first X‐ray crystallographic structure of a mouse γδ TCR bound to its ligand, the nonclassical MHC molecule T22 mentioned above, was solved it was found to have a rather unusual mode of antigen recognition. The extended CDR3 loop of the δ chain, particularly the Dδ2 segment encoded by a nonmutated (germline) sequence, mediated most of the binding with a minor contribution also made by the CDR3 of the γ human γδ TCR, in this case binding to MICA, indicated a focus on CDR1 and CDR2 rather than CDR3 of the δ chain. We will need to wait until more structures are solved before the spectrum of binding sites used by γδ TCRs can be better appreciated.
A particular subset of γδ cells in humans always use the Vγ9 and Vδ2 gene segments (despite utilizing different D and J gene segments). This subset can expand in vivo to comprise a majority of the circulating γδ T‐cells during a diverse range of infections. These Vγ9Vδ2 T‐cells have been shown to recognize phosphoantigens, including a number of such antigens produced by several human pathogens including Mycobacterium tuberculosis and Plasmodium malariae.