Intravenous immunoglobulin induces IgG internalization by tolerogenic myeloid dendritic cells that secrete IL-10 and expand Fc-specific regulatory T cells.

Abstract

Intravenous immunoglobulin (IVIG) is used as an immunomodulatory agent in many inflammatory conditions including Multisystem Inflammatory Syndrome-Children (MIS-C) and Kawasaki disease (KD). However, the exact mechanisms underlying its anti-inflammatory action are incompletely characterized. Here, we show that in KD, a pediatric acute vasculitis that affects the coronary arteries, IVIG induces a repertoire of natural Treg that recognize immunodominant peptides in the Fc heavy chain constant region. To address which antigen-presenting cell (APC) populations present Fc peptides to Treg, we studied the uptake of IgG by innate cells in subacute KD patients 2 weeks after IVIG and in children 1.6-14 years after KD. Healthy adults served as controls. IgG at high concentrations was internalized predominantly by two myeloid dendritic cell (DC) lineages, CD14+ cDC2 and ILT-4+ CD4+ tmDC mostly through Fcγ receptor (R) II and to a lesser extent FcγRIII. Following IgG internalization, these two DC lineages secreted IL-10 and presented processed Fc peptides to Treg. The validation of IVIG function in expanding Fc-specific Treg presented by CD14+ cDC2 and ILT-4+ CD4+ tmDC was addressed in a small cohort of patients with MIS-C. Taken together, these results suggest a novel immune regulatory function of IgG in activating tolerogenic innate cells and expanding Treg, which reveals an important anti-inflammatory mechanism of action of IVIG.

• Authors: Li-En Hsieh, Jaeyoon Song, Adriana H Tremoulet, Jane C Burns, Alessandra Franco
• Journal: Clinical and experimental immunology (Clin Exp Immunol) Vol. 208 Issue 3 Pg. 361-371 (06 23 2022) ISSN: 1365-2249 [Electronic] England
• PMID: 35536993 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.

Chemical References

• Anti-Inflammatory Agents
• Immunoglobulins, Intravenous
• Interleukin-10

Topics

• Adult
• Anti-Inflammatory Agents (therapeutic use)
• Child
• Dendritic Cells
• Humans
• Immunoglobulins, Intravenous (pharmacology, therapeutic use)
• Interleukin-10
• Mucocutaneous Lymph Node Syndrome
• T-Lymphocytes, Regulatory