PT  - JOURNAL ARTICLE
AU  - Lu, Jinghua
AU  - Van Laethem, François
AU  - Saba, Ingrid
AU  - Chu, Jonathan
AU  - Tikhonova, Anastasia N.
AU  - Bhattacharya, Abhisek
AU  - Singer, Alfred
AU  - Sun, Peter D.
TI  - Structure of MHC-Independent TCRs and Their Recognition of Native Antigen CD155
AID  - 10.4049/jimmunol.1901084
DP  - 2020 Jun 15
TA  - The Journal of Immunology
PG  - 3351--3359
VI  - 204
IP  - 12
4099  - http://www.jimmunol.org/content/204/12/3351.short
4100  - http://www.jimmunol.org/content/204/12/3351.full
SO  - J. Immunol.2020 Jun 15; 204
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.