An HLA-E-targeted TCR bispecific molecule redirects T cell immunity against Mycobacterium tuberculosis

Peptides presented by HLA-E, a molecule with very limited polymorphism, represent attractive targets for T cell receptor (TCR)-based immunotherapies to circumvent the limitations imposed by the high polymorphism of classical HLA genes in the human population. Here, we describe a TCR-based bispecific...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 19; p. e2318003121
Main Authors:	Paterson, Rachel L, La Manna, Marco P, Arena De Souza, Victoria, Walker, Andrew, Gibbs-Howe, Dawn, Kulkarni, Rakesh, Fergusson, Joannah R, Mulakkal, Nitha Charles, Monteiro, Mauro, Bunjobpol, Wilawan, Dembek, Marcin, Martin-Urdiroz, Magdalena, Grant, Tressan, Barber, Claire, Garay-Baquero, Diana J, Tezera, Liku Bekele, Lowne, David, Britton-Rivet, Camille, Pengelly, Robert, Chepisiuk, Natalia, Singh, Praveen K, Woon, Amanda P, Powlesland, Alex S, McCully, Michelle L, Caccamo, Nadia, Salio, Mariolina, Badami, Giusto Davide, Dorrell, Lucy, Knox, Andrew, Robinson, Ross, Elkington, Paul, Dieli, Francesco, Lepore, Marco, Leonard, Sarah, Godinho, Luis F
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 07-05-2024
Subjects:	Bacterial Proteins - genetics Bacterial Proteins - immunology Bacterial Proteins - metabolism Biological Sciences Histocompatibility antigen HLA Histocompatibility Antigens Class I - immunology Histocompatibility Antigens Class I - metabolism HLA-E Antigens Human populations Humans Immunity Immunotherapy INHA gene Lymphocytes Lymphocytes T Medical innovations Mycobacterium tuberculosis Mycobacterium tuberculosis - immunology Peptides Polymorphism Receptors, Antigen, T-Cell - immunology Receptors, Antigen, T-Cell - metabolism T cell receptors T-Lymphocytes - immunology Tuberculosis Tuberculosis - immunology T cell receptor immunotherapy tuberculosis HLA-E
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Summary:	Peptides presented by HLA-E, a molecule with very limited polymorphism, represent attractive targets for T cell receptor (TCR)-based immunotherapies to circumvent the limitations imposed by the high polymorphism of classical HLA genes in the human population. Here, we describe a TCR-based bispecific molecule that potently and selectively binds HLA-E in complex with a peptide encoded by the gene of (Mtb), the causative agent of tuberculosis in humans. We reveal the biophysical and structural bases underpinning the potency and specificity of this molecule and demonstrate its ability to redirect polyclonal T cells to target HLA-E-expressing cells transduced with mycobacterial as well as primary cells infected with virulent Mtb. Additionally, we demonstrate elimination of Mtb-infected cells and reduction of intracellular Mtb growth. Our study suggests an approach to enhance host T cell immunity against Mtb and provides proof of principle for an innovative TCR-based therapeutic strategy overcoming HLA polymorphism and therefore applicable to a broader patient population.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Lalita Ramakrishnan, University of Cambridge, Cambridge, United Kingdom; received October 25, 2023; accepted March 8, 2024
ISSN:	0027-8424 1091-6490 1091-6490
DOI:	10.1073/pnas.2318003121