An autonomous CDR3δ is sufficient for recognition of the nonclassical MHC class I molecules T10 and T22 by γδ T cells

It remains unclear whether gamma delta T cell antigen receptors (TCRs) detect antigens in a way similar to antibodies or alpha beta TCRs. Here we show that reactivity between the G8 and KN6 gamma delta TCRs and the major histocompatibility complex class Ib molecule T22 could be recapitulated, with retention of wild-type ligand affinity, in an alpha beta TCR after grafting of a G8 or KN6 complementarity-determining region 3-delta (CDR3 delta) loop in place of the CDR3 alpha loop of an alpha beta TCR. We also found that a shared sequence motif in CDR3 delta loops of all T22-reactive gamma delta TCRs bound T22 in energetically distinct ways, and that T10(d), which bound G8 with weak affinity, was converted into a high-affinity ligand by a single point mutation. Our results demonstrate unprecedented autonomy of a single CDR3 loop in antigen recognition.