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

Stephanie J. Hanna, Terri C. Thayer, Emma J.S. Robinson, Ngoc Nga Vinh, Nigel Williams, Laurie G. Landry, Robert Andrews, Qi Zhuang Siah, Pia Leete, Rebecca Wyatt, Martina A. McAteer, Maki Nakayama, F. Susan Wong, Jennie H.M. Yang, Timothy I.M. Tree, Johnny Ludvigsson, Colin M. Dayan, Danijela Tatovic*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number1276255
JournalFrontiers in Immunology
Volume14
DOIs
Publication statusPublished - 2023

Keywords

  • immunomodulation
  • nanoparticles
  • proinsulin peptide
  • scRNAseq
  • type 1 diabetes

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