Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans

Frontiers in Immunology

Immunology

Laurie G. Landry¹  Maki Nakayama¹  Pia Leete²  Rebecca Wyatt²  Timothy I. M. Tree³  Jennie H. M. Yang³  Martina A. McAteer⁴  Emma J. S. Robinson⁵  Danijela Tatovic⁵  Robert Andrews⁵  F. Susan Wong⁵  Colin M. Dayan⁵  Stephanie J. Hanna⁵  Terri C. Thayer⁶  Johnny Ludvigsson⁷  Ngoc-Nga Vinh⁸  Nigel Williams⁸  Qi Zhuang Siah⁹ 

[1] Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO, United States;Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, United Kingdom;Department of Immunobiology, School of Immunology & Microbial Sciences, King’s College London, Guy’s Hospital, London, United Kingdom;Department of Oncology, University of Oxford, Oxford, United Kingdom;Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom;Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom;Department of Biological and Chemical Sciences, Roberts Wesleyan University, Rochester, NY, United States;Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences and Crown Princess Victoria Children´s Hospital, Linköping University, Linköping, Sweden;Division of Psychological Medicine and Clinical Neurosciences, Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom;John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom;

关键词: nanoparticles;    proinsulin peptide;    type 1 diabetes;    immunomodulation;    scRNAseq;   

DOI  :  10.3389/fimmu.2023.1276255

 received in 2023-08-11, accepted in 2023-10-02,  发布年份 2023

来源: Frontiers

【 摘 要 】

Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8+, whilst proinsulin-specific clones were both CD8+ and CD4+. Proinsulin-specific CD8+ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans.

【 授权许可】

Unknown   
Copyright © 2023 Hanna, Thayer, Robinson, Vinh, Williams, Landry, Andrews, Siah, Leete, Wyatt, McAteer, Nakayama, Wong, Yang, Tree, Ludvigsson, Dayan and Tatovic