The role of self-peptides in direct T cell allorecognition
Hossam A. Abdelsamed, Fadi G. Lakkis
Hossam A. Abdelsamed, Fadi G. Lakkis
Published November 1, 2021
Citation Information: J Clin Invest. 2021;131(21):e154096. https://doi.org/10.1172/JCI154096.
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Commentary

The role of self-peptides in direct T cell allorecognition

Abstract

Direct allorecognition, the ability of host T cells to recognize intact allogeneic MHC molecules on transplanted tissues, is often assumed to be less dependent on the peptide bound to the MHC molecule than are other antigen recognition pathways. In this issue of the JCI, Son et al. provide unequivocal, in vivo evidence that direct allorecognition depends on the self-peptides bound to the non-self MHC molecule. The authors demonstrate that the induction of allospecific tolerance required the presentation of self-peptides by the non-self MHC molecule, and that only a handful of these peptides accounted for a sizeable proportion of the immunogenicity of the MHC antigen. These are important findings for transplant immunologists because they provide molecular insights into the biology of direct allorecognition, the prime driver of the alloimmune response to MHC-mismatched grafts, and much-needed tools, peptide–MHC multimers, to track and study polyclonal alloreactive T cells.

Authors

Hossam A. Abdelsamed, Fadi G. Lakkis

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Figure 1

Peptide dependence of the alloimmune response.

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Peptide dependence of the alloimmune response. (A) Direct and indirect a...
(A) Direct and indirect allorecognition is mediated by recipient TCRs. Direct allorecognition involves the binding of self (recipient) TCRs to non-self (donor) MHC molecules loaded with self-peptides, whereas indirect allorecognition is mediated by recipient TCRs that recognize non-self (donor) peptides bound to self (recipient) MHC molecules. (B) X-ray crystal structure binds the TCR and the peptide–MHC complex. Note that the variable domains of the TCR, Vα and Vβ, contact the peptide as well as the regions of the MHC molecule surrounding the peptide-binding groove. Figure created in Biorender. Protein Data Bank accession: 2CKB. (C) Direct T cell alloreactivity is the summation of many nondominant T cell clones (yellow), a small number of dominant T cell clones (blue), or an intermediate number of nondominant and dominant T cell clones (red). The experiments by Son et al. (16) suggest alloreactivity is the intermediate scenario (red).