Characterization of HLA-DR- and TCR-binding residues of an immunodominant and genetically permissive peptide of the 16-kDa protein of Mycobacterium tuberculosis

Nadia Caccamo, Serena Meraviglia, Carmela La Mendola, Szylvia Bosze, Ferencz Hudecz, Juraj Ivanyi, Francesco Dieli, Alfredo Salerno

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The 16-kDa protein of Mycobacterium tuberculosis represents an important antigenic target during bacillary latency and, consequently, should be considered as candidate subunit vaccine component. In this study, we have used CD4 T cell clones that recognize the peptide p91-110, an immunodominant and genetically permissive epitope, in the context of five different HLA-DR molecules and truncated and substituted variants of this peptide, to identify the minimal binding sequence (HLA-DR-binding core) and the minimal stimulatory sequence (TCR-binding core), as well as the residues that contact HLA-DR molecules and the TCR. We have found a common 9-mer sequence, spanning amino acids 93-101, as the binding core for HLA-DR1, -DR11, -DR13 and -DR7, but a longer (13-mer) sequence spanning amino acids 92-104 was required for binding to the HLA-DR15 molecules. F93 was required for binding to all the tested HLA-DR molecules, hence allowing us to identify it as the N-terminal primary anchor residue (P1). Additionally, the binding requirements for other residues varied considerably between the tested alleles: A94 for HLA-DR15, V99 for HLA-DR1, -DR15, -DR11 and -DR7, R100 for HLA-DR11 and -DR13, and L104 for HLA-DR15. Concerning the residues of p91-110 peptide required for binding to the TCR, the pepscan analysis results would support the contention that P(-1)E92, P6 F98 would be important TCR contact sites because their substitutions led to full loss of T cell activation. Moreover, P8 R100 is found to be critical residue in binding to HLA-DR11- and -DR13-restricted T cell clones, without influencing binding to the relevant HLA-DR molecule. Our results could be useful to design peptides with altered HLA anchor residues or TCR interaction sites to achieve remarkable increase in activity and to study their vaccine potential.

Original languageEnglish
Pages (from-to)2220-2229
Number of pages10
JournalEuropean journal of immunology
Volume34
Issue number8
DOIs
Publication statusPublished - Aug 2004

Keywords

  • 16-kDa M. tuberculosis antigen
  • Binding
  • CD4 T cells
  • HLA-DR
  • TCR

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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