Inhibition of a mitochondrial enzyme during multiple sclerosis treatment modulates antigen-specific T cell responses in an affinity-dependent fashion.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8⁺T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8⁺T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.

Significance: The role of metabolic processes during T cell activation has been increasingly acknowledged, and recent data suggest an impact of T cell immunometabolism on T cell function and T cell-mediated autoimmunity. The factors regulating metabolic function in T cells are not clear, however. We identify the nuclear receptor Nur77 as central regulator of T cell immunometabolism, controlling oxidative phosphorylation and aerobic glycolysis during T cell activation. Functionally, Nur77 restricts murine and human T cell activation and proliferation and limits inflammation in autoimmune conditions in animal models of CNS autoimmunity, contact dermatitis, and arthritis. These findings identify Nur77 as a central regulator of T cell immunometabolism that restricts T cell-mediated autoimmunity, which might open up new avenues for a more tailored therapeutic approach.

Objective: To evaluate the effect of dimethyl fumarate (DMF; Tecfidera, Biogen, Weston, MA) on CD4⁺ and CD8⁺ T cell subsets in patients with multiple sclerosis (MS). Methods: Peripheral lymphocyte subsets, including CD4⁺ and CD8⁺ memory cells and T helper (T_H) cells T_H1, T_H2, T_H17, and peripheral regulatory T cell (pT_reg) subpopulations were analyzed before and 6 months after onset of DMF treatment. Results: CD4⁺ and CD8⁺ memory T cells were preferentially decreased compared to naive CD4⁺ and CD8⁺ T cell populations. Within the CD4⁺ memory T cell population, frequencies of T_H1 cells were decreased, whereas those of T_H2 cells were increased and those of T_H17 cells remained unaltered. Accordingly, we observed decreased production of interferon γ, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-22 by CD4⁺ T cells under DMF treatment, whereas the frequency of IL-4- and IL-17A-producing CD4⁺ T cells remained unchanged. With regard to regulatory T cells, proportions of pT_reg increased following DMF treatment. Conclusion: Our data demonstrate that DMF treatment of patients with MS affects predominantly memory T cells accompanied by a shift in T_H cell populations, resulting in a shift toward anti-inflammatory responses. These findings indicate that monitoring of memory subsets might enhance vigilance of impaired antiviral immunity and that patients with T_H1-driven disease might preferentially benefit from DMF treatment. Classification of Evidence: This study provides Class IV evidence that DMF might preferentially reduce CD4⁺ and CD8⁺ memory T cells in MS.