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

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...

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Published in:Frontiers in immunology 2023-04, Vol.14, p.1177722-1177722
Main Authors: Solé, Patricia, Parras, Daniel, Yamanouchi, Jun, Garnica, Josep, Garabatos, Nahir, Moro, Joel, Montaño, Javier, Mondal, Debajyoti, Fandos, César, Yang, Yang, Serra, Pau, Santamaria, Pere
Format: Article
Language:English
Subjects:
antigen-specific tolerance
CD4-Positive T-Lymphocytes
Diabetes Mellitus, Type 1
Epitopes
Histocompatibility Antigens Class II
Humans
Immunology
immunoregulation
Insulin - metabolism
nanomedicine
peptide-major histocompatibility complex (pMHC) molecules
Peptides
T-Lymphocytes, Helper-Inducer
T-regulatory type 1 (TR1) cells
type 1 diabetes
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Summary: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 (IA ) 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 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.
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2023.1177722