Interferon-γ-induced tolerogenic dendritic cells ameliorate autoimmune neuroinflammation and suppress T-cell...

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by immune-mediated demyelination and neuroinflammation resulting from the breakdown of self-tolerance. Tolerogenic dendritic cells (tolDC) have emerged as a promising therapeutic strategy to restore antigen-specific immune tolerance; however, generating stable tolDC under inflammatory conditions remains challenging. Although interferon (IFN)-γ is traditionally regarded as a pro-inflammatory cytokine, accumulating evidence indicates that it can also exert protective and immunoregulatory functions in specific cellular and disease contexts. Here, we investigated whether low-dose IFN-γ directly programs dendritic cells (DC) toward a stable tolerogenic phenotype with therapeutic relevance for MS.

Murine bone marrow-derived DC were differentiated in the presence of IFN-γ and evaluated for phenotype, cytokine production, and T-cell modulatory capacity. Therapeutic efficacy was assessed in experimental autoimmune encephalomyelitis (EAE). Translational relevance was examined using monocyte-derived DC from treatment-naïve MS patients and healthy donors (HD).

IFN-γ-conditioned DC displayed reduced expression of co-stimulatory molecules and MHC-II, increased PD-L1 expression, and diminished pro-inflammatory cytokine production. Functionally, these cells suppressed myelin antigen-driven CD4⁺ T-cell proliferation and activation while promoting FoxP3⁺ regulatory T-cell differentiation. Adoptive transfer of myelin-derived peptide-loaded IFN-γ-conditioned DC significantly ameliorated established EAE and induced sustained clinical improvement, even after inflammatory challenge, demonstrating phenotypic and functional stability. In human studies, IFN-γ induced comparable tolerogenic phenotypes in DC from MS patients and HD; however, only MS-derived IFN-γ-conditioned DC effectively suppressed CD4⁺ and CD8⁺ T-cell responses. Residual CD80 expression correlated with T1 lesion burden.

Collectively, these findings uncover a previously underappreciated context-dependent immunoregulatory role of IFN-γ in DC biology and immune tolerance. Furthermore, IFN-γ-induced DC emerge as a promising therapeutic strategy to restore immune tolerance in MS.