title: The identification of a common pathogen-specific HLA class I A*0201-restricted cytotoxic T cell epitope encoded within the heat shock protein 65.
abstract: 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(9(369)), is identical in a large number of pathogenic bacteria, and is recognized in a CD8-independent fashion. Mhsp65(9(369)) 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.
authors.affiliation: Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm, Sweden. jehad.charo@mtc.ki.se
authors.forename: J
authors.initials: J
authors.lastname: Charo
authors.forename: A
authors.initials: A
authors.lastname: Geluk
authors.forename: M
authors.initials: M
authors.lastname: Sundbäck
authors.forename: B
authors.initials: B
authors.lastname: Mirzai
authors.forename: A D
authors.initials: AD
authors.lastname: Diehl
authors.forename: K J
authors.initials: KJ
authors.lastname: Malmberg
authors.forename: A
authors.initials: A
authors.lastname: Achour
authors.forename: S
authors.initials: S
authors.lastname: Huriguchi
authors.forename: K E
authors.initials: KE
authors.lastname: van Meijgaarden
authors.forename: J W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: N
authors.initials: N
authors.lastname: Beekman
authors.forename: P
authors.initials: P
authors.lastname: van Veelen
authors.forename: F
authors.initials: F
authors.lastname: Ossendorp
authors.forename: T H
authors.initials: TH
authors.lastname: Ottenhoff
authors.forename: R
authors.initials: R
authors.lastname: Kiessling
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001426:Bacterial Proteins; D002460:Cell Line; D018834:Chaperonin 60; D018833:Chaperonins / Q000737:chemistry / Q000276:immunology*; D003546:Cysteine Endopeptidases / Q000502:physiology; D018984:Epitopes, T-Lymphocyte; D005260:Female; D015234:HLA-A Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen; D006801:Humans; D007114:Immunization; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000502:physiology; D009161:Mycobacterium / Q000276:immunology; D046988:Proteasome Endopeptidase Complex; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D018834:Chaperonin 60; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D009097:Multienzyme Complexes; D019444:Vaccines, DNA; C074119:heat-shock protein 65, Mycobacterium; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D018833:Chaperonins