Depletion of CD4 T cells provides therapeutic benefits in aged mice after ischemic stroke

• Published in: Experimental neurology 2020-04, Vol.326, p.113202-113202, Article 113202
• Main Authors: Harris, Nia M., Roy-O'Reilly, Meaghan, Ritzel, Rodney M., Holmes, Aleah, Sansing, Lauren H., O'Keefe, Lena M., McCullough, Louise D., Chauhan, Anjali
• Format: Article
• Language: English
• Subjects: Age; Aging; Animals; Behavior, Animal; Brain Chemistry; Brain Ischemia - psychology; Brain Ischemia - therapy; CD4 T cells; CD4-Positive T-Lymphocytes; Chemokines - biosynthesis; CXCL10; Cytokines - biosynthesis; Female; Infarction, Middle Cerebral Artery - metabolism; Inflammation; Inflammation - metabolism; Inflammation - pathology; Male; Mice; Mice, Inbred C57BL; Stroke; Stroke - psychology; Stroke - therapy; Treatment Outcome
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2020.113202

T-lymphocytes have a multifaceted role in ischemic stroke, but the majority of studies have been conducted in young mice, which may limit the translational value of these findings. Previous studies have shown that aging results in T cell dysfunction, leading to enhanced production of pro-inflammatory cytokines and chemokines, including interferon gamma (IFN-γ) and interferon-gamma-inducible protein (IP-10). This study assessed the role of T cells and pro-inflammatory factors on histologic and functional outcomes in an aged mouse model. Levels of IP-10 were measured in the brain and serum of young and aged male mice following middle cerebral artery occlusion (MCAo) or sham surgery. Additionally, IP-10 levels were evaluated in stroke patients. To directly determine the role of brain-infiltrating T cells after stroke, a separate cohort of aged male and female animals received either an anti-CD4 depletion antibody or IgG isotype control at 72 and 96 h following experimental stroke. Behavioral assessments were performed on day 7 post-MCAo. CD4 T cell depletion resulted in improved behavioral outcomes, despite the lack of differences in infarct size between the isotype control and anti-CD4 antibody treated stroke groups. Circulating IP-10 levels were increased in both humans and mice with age and stroke, and depletion of CD4 T cells led to a reduction in IFN-γ and IP-10 levels in mice. Since anti-CD4 treatment was administered three days after stroke onset, targeting this inflammatory pathway may be beneficial to aged stroke patients who present outside of the current time window for thrombolysis and thrombectomy. •Aging alters the immunological response to stroke.•Aged animals and humans have poorer outcomes after stroke.•The CD4-IFNy-IP-10 pathway propagates the post-stroke inflammatory cascade.•CD4 depletion during peak inflammation resulted in improved functional outcomes in both male and female aged mice.•Therapies targeting this inflammatory pathway should be explored.