title: The TB-specific CD4(+) T cell immune repertoire in both cynomolgus and rhesus macaques largely overlap with humans.
abstract: Non-human primate (NHP) models of tuberculosis (TB) immunity and pathogenesis, especially rhesus and cynomolgus macaques, are particularly attractive because of the high similarity of the human and macaque immune systems. However, little is known about the MHC class II epitopes recognized in macaques, thus hindering the establishment of immune correlates of immunopathology and protective vaccination. We characterized immune responses in rhesus macaques vaccinated against and/or infected with Mycobacterium tuberculosis (Mtb), to a panel of antigens currently in human vaccine trials. We defined 54 new immunodominant CD4(+) T cell epitopes, and noted that antigens immunodominant in humans are also immunodominant in rhesus macaques, including Rv3875 (ESAT-6) and Rv3874 (CFP10). Pedigree and inferred restriction analysis demonstrated that this phenomenon was not due to common ancestry or inbreeding, but rather presentation by common alleles, as well as, promiscuous binding. Experiments using a second cohort of rhesus macaques demonstrated that a pool of epitopes defined in the previous experiments can be used to detect T cell responses in over 75% of individual monkeys. Additionally, 100% of cynomolgus macaques, irrespective of their latent or active TB status, responded to rhesus and human defined epitope pools. Thus, these findings reveal an unexpected general repertoire overlap between MHC class II epitopes recognized in both species of macaques and in humans, showing that epitope pools defined in humans can also be used to characterize macaque responses, despite differences in species and antigen exposure. The results have general implications for the evaluation of new vaccines and diagnostics in NHPs, and immediate applicability in the setting of macaque models of TB.
authors.affiliation: Department of Biology, CSUSM, San Marcos, CA 92096, USA; La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037, USA. Electronic address: bmothe@csusm.edu.
authors.forename: Bianca R
authors.initials: BR
authors.lastname: Mothé
authors.affiliation: La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037, USA.
authors.forename: Cecilia S
authors.initials: CS
authors.lastname: Lindestam Arlehamn
authors.affiliation: Department of Biology, CSUSM, San Marcos, CA 92096, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Dow
authors.affiliation: La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037, USA.
authors.forename: Myles B C
authors.initials: MBC
authors.lastname: Dillon
authors.affiliation: Wisconsin National Primate Research Center and Department of Pathology and Laboratory Medicine, UW-Madison, Madison, WI 53706, USA.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Wiseman
authors.affiliation: Wisconsin National Primate Research Center and Department of Pathology and Laboratory Medicine, UW-Madison, Madison, WI 53706, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bohn
authors.affiliation: Wisconsin National Primate Research Center and Department of Pathology and Laboratory Medicine, UW-Madison, Madison, WI 53706, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Karl
authors.affiliation: Tulane National Primate Research Center, Covington, LA 70433, USA.
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Golden
authors.affiliation: Department of Biology, CSUSM, San Marcos, CA 92096, USA.
authors.forename: Trey
authors.initials: T
authors.lastname: Gilpin
authors.affiliation: Tulane National Primate Research Center, Covington, LA 70433, USA.
authors.forename: Taylor W
authors.initials: TW
authors.lastname: Foreman
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15216, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rodgers
authors.affiliation: Tulane National Primate Research Center, Covington, LA 70433, USA; Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University Baton Rouge, LA 70803, USA.
authors.forename: Smriti
authors.initials: S
authors.lastname: Mehra
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Department of Pediatrics and Child Health, University of Cape Town, Cape Town 7925, South Africa.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15216, USA.
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn
authors.affiliation: Tulane National Primate Research Center, Covington, LA 70433, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kaushal
authors.affiliation: Wisconsin National Primate Research Center and Department of Pathology and Laboratory Medicine, UW-Madison, Madison, WI 53706, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: O'Connor
authors.affiliation: La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001500:BCG Vaccine / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D004195:Disease Models, Animal; D058501:Enzyme-Linked Immunospot Assay; D018604:Epitope Mapping; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D016056:Immunodominant Epitopes; D059425:Interferon-gamma Release Tests; D008252:Macaca fascicularis; D008253:Macaca mulatta; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D013045:Species Specificity; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes
keywords: CD4(+); Epitopes; Non-human primate