TNFα promotes brain-predominant EAE independent of IFNγ and IL-17A in HLA-DR3 transgenic mice.

Authors

Ti-Ara J Turner, Stephanie R Peterson, Lian E Alt, Leeann S Aguilar Meza, David K Meyerholz, Shailesh K Shahi, Ashutosh K Mangalam

Published in

Journal of immunology (Baltimore, Md. : 1950). Volume 215. Issue 10. Oct 01, 2026.

Abstract

Multiple sclerosis (MS) is thought to be mediated by human leukocyte antigen (HLA) class II-restricted autoreactive CD4 T cells producing interleukin (IL)-17A and/or interferon γ (IFNγ), but the necessity of these cytokines for disease pathogenesis is unclear. Utilizing HLA-DR3 (DRβ1*0301) transgenic mice lacking IFNγ or IL-17A in experimental autoimmune encephalomyelitis (EAE), a model of MS, we found that neither cytokine is essential for disease induction, although both have distinct roles. The absence of IFNγ caused atypical, brain-predominant EAE characterized by high levels of IL-17A, while the absence of IL-17A resulted in classical EAE, targeting the spinal cord. To assess whether IL-17A drives atypical EAE in the absence of IFNγ, we generated HLA-DR3.IFNγ-/-.IL-17A-/- double knockout (DKO) mice. DKO mice developed atypical EAE with brain infiltration and inflammation of the brainstem and cerebellum, indicating that IL-17A is dispensable for brain-predominant disease in the absence of IFNγ. DKO mice exhibited significant CD4 T cell infiltration and increased expression of CD4 T cell-associated genes at peak disease. Prior to central nervous system infiltration, CD4 T cell accumulated in the spleen and inguinal lymph nodes of DKO mice, where they exhibited an altered cytokine milieu and upregulated genes involved in recruitment, activation, and migration to the brain. DKO mice exhibited elevated expression of tumor necrosis factor α (TNFα), granulocyte-macrophage colony-stimulating factor, and IL-17F; however, only TNFα inhibition ameliorated atypical disease. Together, our findings indicate TNFα promotes brain-predominant inflammatory pathology in the absence of IFNγ and IL-17A.

PMID:
42876168
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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