The study of high-affinity TCRs reveals duality in T cell recognition of antigen: Specificity and degeneracy

David L. Ponermeyer, K. Scott Weber, David M Kranz, Paul M. Allen

Research output: Contribution to journalArticle

Abstract

TCRs exhibit a high degree of Ag specificity, even though their affinity for the peptide/MHC ligand is in the micromolar range. To explore how Ag specificity is achieved, we studied murine T cells expressing high-affinity TCRs engineered by in vitro evolution for binding to hemoglobin peptide/class II complex (Hb/I-Ek). These TCRs were shown previously to maintain Ag specificity, despite having up to 800-fold higher affinity. We compared the response of the high-affinity TCRs and the low-affinity 3.L2 TCR toward a comprehensive set of peptides containing single substitutions at each TCR contact residue. This specitcity analysis revealed that the increase in affinity resulted in a dramatic increase in the number of stimulatory peptides. The apparent discrepancy between observed degeneracy in the recognition of single amino acid-substituted Hb peptides and overall Ag specificity of the high-affinity TCRs was examined by generating chimeric peptides between the stimulatory Hb and nonstimulatory moth cytochrome c peptides. These experiments showed that MHC anchor residues significantly affected TCR recognition of peptide. The high-affinity TCRs allowed us to estimate the affinity, in the millimolar range, of immunologically relevant interactions of the TCR with peptide/MHC ligands that were previously unmeasurable because of their weak nature. Thus, through the study of high-affinity TCRs, we demonstrated that a TCR is more tolerant of single TCR contact residue substitutions than other peptide changes, revealing that recognition of Ag by T cells can exhibit both specificity and degeneracy.

Original languageEnglish (US)
Pages (from-to)6911-6919
Number of pages9
JournalJournal of Immunology
Volume177
Issue number10
StatePublished - Nov 15 2006

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T-Lymphocytes
Antigens
Peptides
Ligands
Moths
Cytochromes c
Hemoglobins
Amino Acids

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

The study of high-affinity TCRs reveals duality in T cell recognition of antigen : Specificity and degeneracy. / Ponermeyer, David L.; Weber, K. Scott; Kranz, David M; Allen, Paul M.

In: Journal of Immunology, Vol. 177, No. 10, 15.11.2006, p. 6911-6919.

Research output: Contribution to journalArticle

Ponermeyer, David L. ; Weber, K. Scott ; Kranz, David M ; Allen, Paul M. / The study of high-affinity TCRs reveals duality in T cell recognition of antigen : Specificity and degeneracy. In: Journal of Immunology. 2006 ; Vol. 177, No. 10. pp. 6911-6919.
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