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

Abstract

It remains unclear whether γδ T cell antigen receptors (TCRs) detect antigens in a way similar to antibodies or αβ TCRs. Here we show that reactivity between the G8 and KN6 γδ TCRs and the major histocompatibility complex class Ib molecule T22 could be recapitulated, with retention of wild-type ligand affinity, in an αβ TCR after grafting of a G8 or KN6 complementarity-determining region 3-δ (CDR3δ) loop in place of the CDR3α loop of an αβ TCR. We also found that a shared sequence motif in CDR3δ loops of all T22-reactive γδ TCRs bound T22 in energetically distinct ways, and that T10d, 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.

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Figure 1: Three-dimensional structure of the G8 γδ TCR in complex with the MHC class Ib molecule T22.
Figure 2: Transfer of CDR3δ onto CDR3α.
Figure 3: CDR3δ grafted into the αβ TCR retains wild-type affinity for T10 and T22 ligands.
Figure 4: Heterogeneous energetic 'landscapes' of the interactions of G8 and KN6 CDR3δ with T10 and T22.
Figure 5: The G8 γδ TCR binds to strong and weak stimulatory ligands with different affinity.
Figure 6: Substitutions responsible for differential G8 γδ TCR binding and stimulation by T22 and T10b versus T10d.
Figure 7: A single amino acid substitution converts T10d into a strong G8 γδ TCR agonist.

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Acknowledgements

Supported by the National Institutes of Health (R01 AI65504 to K.C.G. and R01 AI073922 to E.J.A.) and the Howard Hughes Medical Institute (K.C.G.).

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E.J.A. designed, did and analyzed experiments; P.S. designed, did and analyzed circular dichroism experiments; S.S. assisted in cell-stimulation assays; Y.-H.C. provided intellectual insight; and E.J.A. and K.C.G. provided intellectual guidance and prepared the manuscript.

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Correspondence to Erin J Adams or K Christopher Garcia.

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Adams, E., Strop, P., Shin, S. et al. An autonomous CDR3δ is sufficient for recognition of the nonclassical MHC class I molecules T10 and T22 by γδ T cells. Nat Immunol 9, 777–784 (2008). https://doi.org/10.1038/ni.1620

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