Impaired T Follicular Regulatory Cell Function and Enhanced T Follicular Helper Cell Activity in Experimental Autoimmune Encephalomyelitis: Mechanistic Insights into CNS Autoimmunity

TL;DR

This study explores how specific immune cells contribute to autoimmune brain inflammation in a mouse model of multiple sclerosis.

Contribution

The study reveals impaired T follicular regulatory cells and increased T follicular helper cells linked to CNS autoimmunity and elevated IL-21 expression.

Findings

Increased T follicular helper-like cells correlate with CNS inflammation and demyelination.

Reduced T follicular regulatory-like cells indicate impaired immune tolerance.

Elevated IL-21 mRNA suggests B cell activation and antibody-mediated responses.

Abstract

Multiple sclerosis is a chronic immune-mediated central nervous system disorder marked by neuroinflammation, demyelination, and neurodegeneration, and effectively modeled by experimental autoimmune encephalomyelitis. The objective of this study was to elucidate the roles of T follicular helper and T follicular regulatory cells in the progression of experimental autoimmune encephalomyelitis and to assess their association with IL-21 expression and central nervous system tissue pathology. In this study, experimental autoimmune encephalomyelitis was induced in 25 adult female C57BL/6 mice. Fluorescent double immunostaining for CXCR5 in combination with PD-1, ICOS, CD4, and FOXP3 was performed, along with the analysis of IL-21 mRNA expression. Histopathological assessment was conducted on the cerebrum, cerebellum, and medulla spinalis to evaluate neuroinflammation and myelin loss. A significant increase in CXCR5+PD-1+ and CXCR5+ICOS+ T follicular helper-like cells was observed in brain tissue, indicating immune activation and T follicular helper cell involvement. Simultaneously, a marked decrease in FOXP3+ T follicular regulatory-like cells suggested impaired immune tolerance and enhanced autoimmune activity. The infiltration of T follicular helper-like cells was identified as a key driver of inflammation and demyelination in the central nervous system. Additionally, the elevated IL-21 mRNA expression highlighted B cell activation and the initiation of antibody-mediated responses. These findings suggest that dysregulation of the T follicular helper/T follicular regulatory axis and elevated IL-21 expression contribute to the immunopathogenesis of experimental autoimmune encephalomyelitis, providing further insight into the mechanisms underlying multiple sclerosis development.

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