TCR Recognition of the Hb(64-76)/I-Ek Determinant: Single Conservative Amino Acid Changes in the Complementarity-Determining Region 3 Dramatically Alter Antigen Fine Specificity

Benjamin L. Hsu, David L. Donermeyer, Paul M. Allen

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

To identify the structural basis of Ag fine specificity, TCR sequences from a panel of Hb(64-76)/I-Ek-specific T cells were compared and found to be restricted in variable (V) gene usage, predominantly using BV1 or BV15 and AV4 or AV10 genes. TCRA and TCRB junctional sequences were extremely diverse. No conservation of length or position was found, which distinguishes this response from others, but correlates with the range of fine specificities that these T cells display. A remarkable subtlety in the recognition of Hb(64-76) was revealed from the study of the response to the D73 variant of Hb(64-76), which contains a conservative change in an MHC anchor residue not affecting the binding affinity to I-Ek. To one group of T cells this determinant was non-cross-reacting with Hb(64-76), whereas another recognized both Ags. Interesting, they all used a different constellation of TCRBV genes than that found in Hb(64-76) recognition. To limit the variability in the anti-Hb(64-76) TCR repertoire, transgenic mice expressing a fixed TCRB rearrangement from a Hb(64-76)-specific T cell were used. In Hb(64-76)-specific TCR from these mice, the endogenous α-chains pairing with the transgenic β-chain were highly restricted in their AV gene usage. A comparison of two pairs of closely related T cells of these endogenous TCR variants, one differing by a single, conservative substitution in the complementarity-detemining region 3 and the other containing a positional switch of two amino acids, revealed dramatically different fine specificities. Overall, these findings highlight the exquisite sensitivity of the TCR-peptide/MHC interaction to subtle alterations in any of the components.

Original languageEnglish
Pages (from-to)2291-2298
Number of pages8
JournalJournal of Immunology
Volume157
Issue number6
StatePublished - Sep 15 1996

Fingerprint Dive into the research topics of 'TCR Recognition of the Hb(64-76)/I-E<sup>k</sup> Determinant: Single Conservative Amino Acid Changes in the Complementarity-Determining Region 3 Dramatically Alter Antigen Fine Specificity'. Together they form a unique fingerprint.

  • Cite this