A class-mismatched TCR bypasses MHC restriction via an unorthodox but fully functional binding geometry.

ABSTRACT: MHC restriction, which describes the binding of TCRs from CD4⁺ T cells to class II MHC proteins and TCRs from CD8⁺ T cells to class I MHC proteins, is a hallmark of immunology. Seemingly rare TCRs that break this paradigm exist, but mechanistic insight into their behavior is lacking. TIL1383I is a prototypical class-mismatched TCR, cloned from a CD4⁺ T cell but recognizing the tyrosinase tumor antigen presented by the class I MHC HLA-A2 in a fully functional manner. Here we find that TIL1383I binds this class I target with a highly atypical geometry. Despite unorthodox binding, TCR signaling, antigen specificity, and the ability to use CD8 are maintained. Structurally, a key feature of TIL1383I is an exceptionally long CDR3β loop that mediates functions tha

SUBMITTER: Singh NK 

PROVIDER: S-EPMC9691722 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature