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.
