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

Front Immunol. 2023 Apr 19:14:1177722. doi: 10.3389/fimmu.2023.1177722. eCollection 2023.

Abstract

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.

Keywords: T-regulatory type 1 (TR1) cells; antigen-specific tolerance; immunoregulation; insulin B-chain; nanomedicine; peptide-major histocompatibility complex (pMHC) molecules; type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes*
  • Diabetes Mellitus, Type 1*
  • Epitopes
  • Histocompatibility Antigens Class II
  • Humans
  • Insulin / metabolism
  • Peptides
  • T-Lymphocytes, Helper-Inducer

Substances

  • Insulin
  • Epitopes
  • Histocompatibility Antigens Class II
  • Peptides