Background/Purpose: Recent studies of human genetics and mouse models have shown that interferon regulatory factor-5 (IRF5) is associated with the development of autoimmune disease. However, the role of IRF5 in their pathogenesis is not fully understood.

Methods: We generated dendritic cells (DCs) with Fms-related tyrosine kinase 3 ligand (Flt-3L) using bone marrow cells from wild type mice or IRF5-/- mice. We stimulated the DCs with toll-like receptor (TLR) ligands and cultured them with CD4+ T cells. We measured T cell cytokines (IFN-gamma, IL-17, IL-4 and IL-2) in the culture supernatant. In separate experiments, we stimulated B cells from wild type mice and IRF5-/- mice with TLR ligands in the presence of IFN-gamma, IFN-beta, IL-4 and IL-17.

Results: TLR7-IRF5 signaling in DCs stimulated CD4+ T cells to release large amounts of type II IFN (IFN-gamma). Concomitantly, IL-2 production from CD4+ T cells was suppressed. This balance of cytokine production was controlled by modulating IL-12 and type I IFN expression through IRF5. By neutralizing IL-12p40 and blocking IFN receptors, production of IFN-gamma was suppressed while that of IL-2 was increased. IFN-gamma enhances IgG2a/c and IgG2b production from B cells stimulated with TLR7 and TLR9 through IRF5-dependent pathways. In addition, dual activation of BCR and TLR7 induces IRF5-dependent enhancement of T-bet, which is responsible for IgG2a production in B cells.

Conclusion: IRF5 promotes Th1-type T cell responses and the production of pathogenic IgG isotypes. In adidition, our results provide a mechanism to explain the low level of T cell IL-2 expression that has previously been linked to lupus pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ifn-regulatory-factor-5-signaling-increases-ifn-gamma-production-and-suppresses-il-2-production-from-cd4-t-cells-and-controls-igg-production-in-b-cells/