Frontiers in Immunology (Apr 2023)

Transcriptional re-programming of insulin B-chain epitope-specific T-follicular helper cells into anti-diabetogenic T-regulatory type-1 cells

  • Patricia Solé,
  • Daniel Parras,
  • Jun Yamanouchi,
  • Josep Garnica,
  • Nahir Garabatos,
  • Joel Moro,
  • Javier Montaño,
  • Debajyoti Mondal,
  • César Fandos,
  • Yang Yang,
  • Yang Yang,
  • Pau Serra,
  • Pere Santamaria,
  • Pere Santamaria

DOI
https://doi.org/10.3389/fimmu.2023.1177722
Journal volume & issue
Vol. 14

Abstract

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Systemic delivery of nanoparticles (NPs) coated with mono-specific autoimmune disease-relevant peptide-major histocompatibility complex class II (pMHCII) molecules can resolve organ inflammation in various disease models in a disease-specific manner without impairing normal immunity. These compounds invariably trigger the formation and systemic expansion of cognate pMHCII-specific T-regulatory type 1 (TR1) cells. By focusing on type 1 diabetes (T1D)-relevant pMHCII-NP types that display an epitope from the insulin B-chain bound to the same MHCII molecule (IAg7) on three different registers, we show that pMHCII-NP-induced TR1 cells invariably co-exist with cognate T-Follicular Helper (TFH)-like cells of quasi-identical clonotypic composition and are oligoclonal, yet transcriptionally homogeneous. Furthermore, these three different TR1 specificities have similar diabetes reversal properties in vivo despite being uniquely reactive against the peptide MHCII-binding register displayed on the NPs. Thus, pMHCII-NP treatment using nanomedicines displaying different epitope specificities results in the simultaneous differentiation of multiple antigen-specific TFH-like cell clones into TR1-like cells that inherit the fine antigenic specificity of their precursors while acquiring a defined transcriptional immunoregulatory program.

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