RORγt-Expressing Pathogenic CD4⁺ T Cells Cause Brain Inflammation during Chronic Colitis

Area of Science:

• Immunology
• Neuroscience
• Gastroenterology

Background:

• Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is associated with neurobehavioral disorders and brain abnormalities.
• The precise mechanisms underlying these neurological complications in IBD remain unclear.
• CD4+ T cell subsets, particularly Th17 cells, are implicated in neuroinflammatory and cognitive conditions like multiple sclerosis and Alzheimer's disease.

Purpose of the Study:

• To investigate the role of CD4+ T lymphocytes in the development of brain pathology during chronic intestinal inflammation.
• To elucidate the contribution of Th17 cells to neuroinflammation and associated neurobehavioral disorders in a mouse model of colitis.

Main Methods:

• Utilized a T cell transfer model of chronic colitis in Rag1-/- mice.
• Analyzed CD4+ T cell infiltration into the brain and correlated it with colitis severity and neurobehavioral deficits.
• Investigated the phenotype of brain-infiltrating CD4+ T cells, focusing on the Th17 transcription factor RORγt.
• Performed adoptive transfer experiments using RORγt-deficient CD4+ T cells.
• Examined dextran sulfate sodium-induced colitis in Rorc mutant mice.

Main Results:

• CD4+ T cells infiltrated the brain of colitic mice in proportion to colitis severity.
• Colitic mice exhibited hypothalamic astrogliosis and neurobehavioral disorders.
• Brain-infiltrating CD4+ T cells expressed RORγt and exhibited a pathogenic Th17 phenotype.
• Transfer of RORγt-deficient CD4+ T cells prevented brain inflammation and neurobehavioral deficits.
• Rorc mutant mice showed reduced brain inflammation and astrogliosis despite more severe colitis.

Conclusions:

• Pathogenic RORγt+ CD4+ T cells, implicated in colitis exacerbation, preferentially migrate to the brain.
• These cells contribute to brain inflammation and neurobehavioral disorders in the context of IBD.
• The findings establish a direct link between gut inflammation severity and neuroinflammation mediated by specific T cell populations.