The identification of a common pathogen‐specific HLA class I A0201‐restricted cytotoxic T cell epitope encoded within the heat shock protein 65

• Published in: European journal of immunology 2001-12, Vol.31 (12), p.3602-3611
• Main Authors: Charo, Jehad, Geluk, Annemieke, Sundbäck, Maria, Mirzai, Babak, Diehl, Alexander D., Malmberg, Karl‐Johan, Achour, Adnane, Huriguchi, Shigetoshi, Meijgaarden, Krista E. van, Drijfhout, Jan‐Wouter, Beekman, Nico, Veelen, Peter van, Ossendorp, Ferry, Ottenhoff, Tom H.M., Kiessling, Rolf
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antigen Presentation; Bacterial Proteins; CD8 antigen; Cell Line; Chaperonin 60; Chaperonins - chemistry; Chaperonins - immunology; Cysteine Endopeptidases - physiology; DNA vaccine; Epitopes, T-Lymphocyte; Female; Heat shock protein 65; histocompatibility antigen HLA; HLA-A Antigens - immunology; HLA-A2 Antigen; Hsp65 protein; Humans; Immunization; Male; MHC class I; Mice; Mice, Transgenic; Models, Molecular; Molecular Sequence Data; Multienzyme Complexes - physiology; Mycobacterium - immunology; Peptide; Proteasome Endopeptidase Complex; T-Lymphocytes, Cytotoxic - immunology; Vaccines, DNA - immunology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/1521-4141(200112)31:12<3602::AID-IMMU3602>3.0.CO;2-L

Bacterial antigens recognized by CD8+ T cells in the context of MHC class I are thought to play a crucial role in protection against pathogenic intracellular bacteria. Here, we demonstrate the induction of HLA‐A*0201‐restricted CD8+ T cell responses against six new high‐affinity HLA‐A*0201‐binding CTL epitopes, encoded within an immunodominant and highly conserved antigen of Mycobacteria, the heat shock protein 65 (hsp65). One of these epitopes, Mhsp65(9369), is identical in a large number of pathogenic bacteria, and is recognized in a CD8‐independent fashion. Mhsp65(9369) could be presented by either mycobacterial hsp65‐pulsed target cells or BCG‐infected macrophages. Interestingly, T cells specific for this epitope did not recognize the corresponding human hsp65 homologue, probably due to structural differences as revealed by modeling studies. Furthermore, in vitro proteasome digestion analyses show that, whereas the mycobacterial hsp65 epitope is efficiently generated, the human hsp65 homologue is not, thus avoiding the induction of autoreactivity. Collectively, these findings describe high‐affinity HLA class I‐binding epitopes that are naturally processed and are recognized efficiently by MHC class I‐restricted CD8+ T cells, providing a rational basis for the development of subunit vaccine strategies against tuberculosis and other intracellular infectious diseases.