Journal Article

Targeting T cell metabolism and polarization to modulate post-stroke immune responses and improve outcomes

Kirsch, Susanne H., Müller, Rolf, Gellrich, Juliane, Ruhnau, Johanna, Schulze, Juliane, Vogelgesang, Antje, Bödecker, Nora, Reich, Imke, Groß, Stefan

2026

Overview

T cells drive post-stroke secondary brain injury, with the Th17/Treg balance shaping post-stroke inflammation. Soraphen A (SorA) inhibits Th17 polarization while preserving Tregs. We examined SorA's effects on post-stroke T cell activation - distinguishing antigen-specific from bystander activation - including inflammatory conditions induced by LPS. Male Nur77 mice (12-14 weeks) underwent tMCAO. At reperfusion, mice received intraperitoneal LPS or vehicle; SorA or vehicle was given 2 h later and daily thereafter. MRI at 16 h and 7 d confirmed infarcts and measured lesion volumes. Functional outcomes were assessed by daily scoring and behavioral tests before surgery and at 2 and 6 d. T cell activation and polarization were analyzed by flow cytometry in brain, lungs, spleen, blood, and lymph nodes at 16 h, 2, 3, and 7 d, with GFP indicating antigen-specific activation. LPS worsened functional outcomes and increased peripheral T cell activation post-stroke. SorA improved functional recovery, reduced peripheral T cell activation and enhanced antigen-specific T cell activation. SorA increased Treg in LPS-treated mice and reversed LPS-induced alterations in both T cell activation and behavior. Soraphen A modulates systemic and organ-specific T cell responses in experimental ischemic stroke and improves outcomes. SorA increases regulatory T cells, reverses LPS-associated T cell activation (CD25, CD69, PD-1) and behavioral deficits, and shifts responses toward antigen-specific T cell receptor-mediated activation. These results support SorA as a promising immunomodulatory strategy to refine post-stroke immunity, extend the therapeutic window, and improve outcomes with potential benefits in the context of post-stroke infections.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animal cognition / Animals / antigen-specific / Antigens / Body temperature / Brain injury / CD25 antigen / CD69 antigen / Cell activation / Cognitive impairment / Disease Models, Animal / Fatty acids / Flow cytometry / GFP / Helper cells / Immunomodulation / Immunoregulation / Infections / Inflammation / Investigations / Ischemia / Lipopolysaccharides / Localization / Lymph nodes / Lymphocyte Activation - drug effects / Lymphocyte Activation - immunology / Lymphocytes / Lymphocytes T / Magnetic resonance imaging / Male / MCAO / Metabolism / Mice / Mice, Inbred C57BL / Mice, Transgenic / Natural products / Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics / Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism / Nur77 / Original Research / PD-1 protein / Polarization / Recovery of function / Reperfusion / Respiration / Soraphen A / Stroke / Stroke - drug therapy / Stroke - immunology / Stroke - metabolism / Surgery / T cell receptors / T-Lymphocytes, Regulatory - drug effects / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - metabolism / Th17 Cells - drug effects / Th17 Cells - immunology / Th17 Cells - metabolism / Veins & arteries