{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T02:47:10Z","timestamp":1787539630526,"version":"build-2736575974"},"reference-count":37,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T00:00:00Z","timestamp":1727740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health","award":["R01AI141315"],"award-info":[{"award-number":["R01AI141315"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background: Novel vaccines targeting the world\u2019s deadliest pathogen Mycobacterium tuberculosis (Mtb) are urgently needed as the efficacy of the Bacillus Calmette\u2013Gu\u00e9rin (BCG) vaccine in its current use is limited. HLA-E is a virtually monomorphic unconventional antigen presentation molecule, and HLA-E-restricted Mtb-specific CD8+ T cells can control intracellular Mtb growth, making HLA-E a promising vaccine target for Mtb. Methods: In this study, we evaluated the frequency and phenotype of HLA-E-restricted Mtb-specific CD4+\/CD8+ T cells in the circulation and bronchoalveolar lavage fluid of two independent non-human primate (NHP) studies and from humans receiving BCG either intradermally or mucosally. Results: BCG vaccination followed by Mtb challenge in NHPs did not affect the frequency of circulating and local HLA-E\u2013Mtb CD4+ and CD8+ T cells, and we saw the same in humans receiving BCG. HLA-E\u2013Mtb T cell frequencies were significantly increased after Mtb challenge in unvaccinated NHPs, which was correlated with higher TB pathology. Conclusions: Together, HLA-E\u2013Mtb-restricted T cells are minimally induced by BCG in humans and rhesus macaques (RMs) but can be elicited after Mtb infection in unvaccinated RMs. These results give new insights into targeting HLA-E as a potential immune mechanism against TB.<\/jats:p>","DOI":"10.3390\/vaccines12101129","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T07:41:49Z","timestamp":1727768509000},"page":"1129","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mtb-Specific HLA-E-Restricted T Cells Are Induced during Mtb Infection but Not after BCG Administration in Non-Human Primates and Humans"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0523-8929","authenticated-orcid":false,"given":"Linda","family":"Voogd","sequence":"first","affiliation":[{"name":"Leiden University Center for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4952-9709","authenticated-orcid":false,"given":"Marjolein","family":"van Wolfswinkel","sequence":"additional","affiliation":[{"name":"Leiden University Center for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iman","family":"Satti","sequence":"additional","affiliation":[{"name":"The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9481-0079","authenticated-orcid":false,"given":"Andrew","family":"White","sequence":"additional","affiliation":[{"name":"UK Health Security Agency, Porton Down, Wiltshire SP4 0JG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Dijkman","sequence":"additional","affiliation":[{"name":"Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1473-9204","authenticated-orcid":false,"given":"Anele","family":"Gela","sequence":"additional","affiliation":[{"name":"South African Tuberculosis Vaccine Initiative, Institute of Infectious Diseases and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town 7925, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2818-9805","authenticated-orcid":false,"given":"Krista","family":"van Meijgaarden","sequence":"additional","affiliation":[{"name":"Leiden University Center for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kees","family":"Franken","sequence":"additional","affiliation":[{"name":"Leiden University Center for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Marshall","sequence":"additional","affiliation":[{"name":"The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Ottenhoff","sequence":"additional","affiliation":[{"name":"Leiden University Center for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Scriba","sequence":"additional","affiliation":[{"name":"South African Tuberculosis Vaccine Initiative, Institute of Infectious Diseases and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town 7925, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2126-5142","authenticated-orcid":false,"given":"Helen","family":"McShane","sequence":"additional","affiliation":[{"name":"The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7014-7660","authenticated-orcid":false,"given":"Sally","family":"Sharpe","sequence":"additional","affiliation":[{"name":"UK Health Security Agency, Porton Down, Wiltshire SP4 0JG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4441-5000","authenticated-orcid":false,"given":"Frank","family":"Verreck","sequence":"additional","affiliation":[{"name":"Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9878-0863","authenticated-orcid":false,"given":"Simone","family":"Joosten","sequence":"additional","affiliation":[{"name":"Leiden University Center for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,1]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2023). Global Tuberculosis Report 2023, World Health Organization."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hunter, R.L., Actor, J.K., Hwang, S.A., Khan, A., Urbanowski, M.E., Kaushal, D., and Jagannath, C. (2018). Pathogenesis and Animal Models of Post-Primary (Bronchogenic) Tuberculosis, A Review. Pathogens, 7.","DOI":"10.3390\/pathogens7010019"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ijid.2017.01.030","article-title":"Experimental animal modelling for TB vaccine development","volume":"56","author":"Cardona","year":"2017","journal-title":"Int. J. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.4049\/jimmunol.1500943","article-title":"Donor Unrestricted T Cells: A Shared Human T Cell Response","volume":"195","author":"Moody","year":"2015","journal-title":"J. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kanevskiy, L., Erokhina, S., Kobyzeva, P., Streltsova, M., Sapozhnikov, A., and Kovalenko, E. (2019). Dimorphism of HLA-E and its Disease Association. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215496"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5082","DOI":"10.1074\/jbc.M208268200","article-title":"HLA-E allelic variants. Correlating differential expression, peptide affinities, crystal structures, and thermal stabilities","volume":"278","author":"Strong","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5199","DOI":"10.1073\/pnas.95.9.5199","article-title":"HLA-E is a major ligand for the natural killer inhibitory receptor CD94\/NKG2A","volume":"95","author":"Lee","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/35869","article-title":"HLA-E binds to natural killer cell receptors CD94\/NKG2A, B and C","volume":"391","author":"Braud","year":"1998","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.it.2022.03.002","article-title":"Antigen presentation by MHC-E: A putative target for vaccination?","volume":"43","author":"Voogd","year":"2022","journal-title":"Trends Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"109233","DOI":"10.1016\/j.isci.2024.109233","article-title":"Mtb HLA-E-tetramer-sorted CD8(+) T cells have a diverse TCR repertoire","volume":"27","author":"Voogd","year":"2024","journal-title":"iScience"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.4049\/jimmunol.2200122","article-title":"Identification of HLA-E Binding Mycobacterium tuberculosis-Derived Epitopes through Improved Prediction Models","volume":"209","author":"Ruibal","year":"2022","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"van Meijgaarden, K.E., Haks, M.C., Caccamo, N., Dieli, F., Ottenhoff, T.H., and Joosten, S.A. (2015). Human CD8+ T-cells recognizing peptides from Mycobacterium tuberculosis (Mtb) presented by HLA-E have an unorthodox Th2-like, multifunctional, Mtb inhibitory phenotype and represent a novel human T-cell subset. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004671"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eabl8881","DOI":"10.1126\/sciimmunol.abl8881","article-title":"HLA-E-restricted SARS-CoV-2-specific T cells from convalescent COVID-19 patients suppress virus replication despite HLA class Ia down-regulation","volume":"8","author":"Yang","year":"2023","journal-title":"Sci. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5852","DOI":"10.4049\/jimmunol.173.9.5852","article-title":"Identification of a human HLA-E-restricted CD8+ T cell subset in volunteers immunized with Salmonella enterica serovar Typhi strain Ty21a typhoid vaccine","volume":"173","author":"Lewinsohn","year":"2004","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1182\/blood.2022017650","article-title":"HLA-E-restricted immune responses are crucial for the control of EBV infections and the prevention of PTLD","volume":"141","author":"Vietzen","year":"2023","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e1382793","DOI":"10.1080\/2162402X.2017.1382793","article-title":"T cells specific for a TAP-independent self-peptide remain naive in tumor-bearing mice and are fully exploitable for therapy","volume":"7","author":"Doorduijn","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"60","DOI":"10.3389\/fimmu.2018.00060","article-title":"T Cells Engaging the Conserved MHC Class Ib Molecule Qa-1(b) with TAP-Independent Peptides Are Semi-Invariant Lymphocytes","volume":"9","author":"Doorduijn","year":"2018","journal-title":"Front Immunol"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"eabg1703","DOI":"10.1126\/sciimmunol.abg1703","article-title":"HLA-E-restricted, Gag-specific CD8(+) T cells can suppress HIV-1 infection, offering vaccine opportunities","volume":"6","author":"Yang","year":"2021","journal-title":"Sci. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Jorgensen, P.B., Livbjerg, A.H., Hansen, H.J., Petersen, T., and Hollsberg, P. (2012). Epstein-Barr virus peptide presented by HLA-E is predominantly recognized by CD8(bright) cells in multiple sclerosis patients. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046120"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"eaaw2607","DOI":"10.1126\/scitranslmed.aaw2607","article-title":"A live-attenuated RhCMV\/SIV vaccine shows long-term efficacy against heterologous SIV challenge","volume":"11","author":"Hansen","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/j.chom.2022.07.013","article-title":"Cytomegalovirus-vaccine-induced unconventional T cell priming and control of SIV replication is conserved between primate species","volume":"30","author":"Malouli","year":"2022","journal-title":"Cell Host Microbe"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"eabe9233","DOI":"10.1126\/science.abe9233","article-title":"Modulation of MHC-E transport by viral decoy ligands is required for RhCMV\/SIV vaccine efficacy","volume":"372","author":"Verweij","year":"2021","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1177\/135965350501000107","article-title":"HIV-1 infection leads to increased HLA-E expression resulting in impaired function of natural killer cells","volume":"10","author":"Nattermann","year":"2005","journal-title":"Antivir. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gela, A., Murphy, M., Rodo, M., Hadley, K., Hanekom, W.A., Boom, W.H., Johnson, J.L., Hoft, D.F., Joosten, S.A., and Ottenhoff, T.H.M. (2022). Effects of BCG vaccination on donor unrestricted T cells in two prospective cohort studies. EBioMedicine, 76.","DOI":"10.1016\/j.ebiom.2022.103839"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3982","DOI":"10.1016\/j.vaccine.2014.04.084","article-title":"Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults","volume":"32","author":"Hatherill","year":"2014","journal-title":"Vaccine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/S1473-3099(24)00143-9","article-title":"Safety of a controlled human infection model of tuberculosis with aerosolised, live-attenuated Mycobacterium bovis BCG versus intradermal BCG in BCG-naive adults in the UK: A dose-escalation, randomised, controlled, phase 1 trial","volume":"24","author":"Satti","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"White, A.D., Sarfas, C., Sibley, L.S., Gullick, J., Clark, S., Rayner, E., Gleeson, F., Catala, M., Nogueira, I., and Cardona, P.J. (2020). Protective Efficacy of Inhaled BCG Vaccination Against Ultra-Low Dose Aerosol M. tuberculosis Challenge in Rhesus Macaques. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12050394"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/s41591-018-0319-9","article-title":"Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques","volume":"25","author":"Dijkman","year":"2019","journal-title":"Nat. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"White, A.D., Sibley, L., Gullick, J., Sarfas, C., Clark, S., Fagrouch, Z., Verschoor, E., Salguero, F.J., Dennis, M., and Sharpe, S. (2021). TB and SIV Coinfection; a Model for Evaluating Vaccine Strategies against TB Reactivation in Asian Origin Cynomolgus Macaques: A Pilot Study Using BCG Vaccination. Vaccines, 9.","DOI":"10.3390\/vaccines9090945"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1002\/cyto.a.24727","article-title":"Extensive flow cytometric immunophenotyping of human PBMC incorporating detection of chemokine receptors, cytokines and tetramers","volume":"103","author":"Ottenhoff","year":"2023","journal-title":"Cytom. A"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.1038\/s41467-018-05459-z","article-title":"Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding","volume":"9","author":"Walters","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41586-019-1817-8","article-title":"Prevention of tuberculosis in macaques after intravenous BCG immunization","volume":"577","author":"Darrah","year":"2020","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/eji.201747184","article-title":"Detailed characterization of human Mycobacterium tuberculosis specific HLA-E restricted CD8(+) T cells","volume":"48","author":"Prezzemolo","year":"2018","journal-title":"Eur. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Sullivan, L.C., Westall, G.P., Widjaja, J.M., Mifsud, N.A., Nguyen, T.H., Meehan, A.C., Kotsimbos, T.C., and Brooks, A.G. (2015). The Presence of HLA-E-Restricted, CMV-Specific CD8+ T Cells in the Blood of Lung Transplant Recipients Correlates with Chronic Allograft Rejection. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135972"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10896","DOI":"10.1073\/pnas.1834449100","article-title":"HLA-E-restricted recognition of cytomegalovirus-derived peptides by human CD8+ cytolytic T lymphocytes","volume":"100","author":"Pietra","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3240","DOI":"10.1002\/eji.200535343","article-title":"Identification of effector-memory CMV-specific T lymphocytes that kill CMV-infected target cells in an HLA-E-restricted fashion","volume":"35","author":"Mazzarino","year":"2005","journal-title":"Eur. J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1126\/science.aac9475","article-title":"Broadly targeted CD8(+) T cell responses restricted by major histocompatibility complex E","volume":"351","author":"Hansen","year":"2016","journal-title":"Science"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/12\/10\/1129\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:08:41Z","timestamp":1760112521000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/12\/10\/1129"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,1]]},"references-count":37,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["vaccines12101129"],"URL":"https:\/\/doi.org\/10.3390\/vaccines12101129","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,1]]}}}