8QFY

Crystal structure of high affinity TCR in complex with pHLA harbouring bacterial peptide

This is a non-PDB format compatible entry.

Summary for 8QFY

• Entry DOI: 10.2210/pdb8qfy/pdb
• Descriptor: HLA class I histocompatibility antigen, alpha chain E, Beta-2-microglobulin, Peptide from inhA, ... (7 entities in total)
• Functional Keywords: t-cell receptor, hla-e, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 189031.57

Authors

Pengelly, R.J.,Robinson, R.A. (deposition date: 2023-09-05, release date: 2024-05-15, Last modification date: 2024-10-16)

Primary citation

Paterson, R.L.,La Manna, M.P.,Arena De Souza, V.,Walker, A.,Gibbs-Howe, D.,Kulkarni, R.,Fergusson, J.R.,Mulakkal, N.C.,Monteiro, M.,Bunjobpol, W.,Dembek, M.,Martin-Urdiroz, M.,Grant, T.,Barber, C.,Garay-Baquero, D.J.,Tezera, L.B.,Lowne, D.,Britton-Rivet, C.,Pengelly, R.,Chepisiuk, N.,Singh, P.K.,Woon, A.P.,Powlesland, A.S.,McCully, M.L.,Caccamo, N.,Salio, M.,Badami, G.D.,Dorrell, L.,Knox, A.,Robinson, R.,Elkington, P.,Dieli, F.,Lepore, M.,Leonard, S.,Godinho, L.F.
An HLA-E-targeted TCR bispecific molecule redirects T cell immunity against Mycobacterium tuberculosis.
Proc.Natl.Acad.Sci.USA, 121:e2318003121-e2318003121, 2024

PubMed Abstract: 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.

PubMed: 38691588
DOI: 10.1073/pnas.2318003121

Experimental method

X-RAY DIFFRACTION (2.33 Å)