RT Journal Article
SR Electronic
T1 Structure of MHC-Independent TCRs and Their Recognition of Native Antigen CD155
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 3351
OP 3359
DO 10.4049/jimmunol.1901084
VO 204
IS 12
A1 Lu, Jinghua
A1 Van Laethem, François
A1 Saba, Ingrid
A1 Chu, Jonathan
A1 Tikhonova, Anastasia N.
A1 Bhattacharya, Abhisek
A1 Singer, Alfred
A1 Sun, Peter D.
YR 2020
UL http://www.jimmunol.org/content/204/12/3351.abstract
AB αβ TCRs, A11 and B12A, recognize CD155 independent of MHC presentation.CDR3 of α- or β-chain alone is insufficient to discriminate against MHC binding.This study reports the structure of αβ TCR in complex with a non-MHC ligand.During normal T cell development in the thymus, αβ TCRs signal immature thymocytes to differentiate into mature T cells by binding to peptide–MHC ligands together with CD4/CD8 coreceptors. Conversely, in MHC and CD4/CD8 coreceptor-deficient mice, the thymus generates mature T cells expressing MHC-independent TCRs that recognize native conformational epitopes rather than linear antigenic-peptides presented by MHC. To date, no structural information of MHC-independent TCRs is available, and their structural recognition of non-MHC ligand remains unknown. To our knowledge in this study, we determined the first structures of two murine MHC-independent TCRs (A11 and B12A) that bind with high nanomolar affinities to mouse adhesion receptor CD155. Solution binding demonstrated the Vαβ-domain is responsible for MHC-independent B12A recognition of its ligand. Analysis of A11 and B12A sequences against various MHC-restricted and -independent TCR sequence repertoires showed that individual V-genes of A11 and B12A did not exhibit preference against MHC-restriction. Likewise, CDR3 alone did not discriminate against MHC binding, suggesting VDJ recombination together with Vα/Vβ pairing determine their MHC-independent specificity for CD155. The structures of A11 and B12A TCR are nearly identical to those of MHC-restricted TCR, including the conformations of CDR1 and 2. Mutational analysis, together with negative-staining electron microscopy images, showed that the CDR regions of A11 and B12A recognized epitopes on D1 domain of CD155, a region also involved in CD155 binding to poliovirus and Tactile in human. Taken together, MHC-independent TCRs adopt canonical TCR structures to recognize native Ags, highlighting the importance of thymic selection in determining TCR ligand specificity.