T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention

Area of Science:

• Immunology
• Neuroscience
• Cell Biology

Background:

• Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are key regulators of multiple sclerosis (MS) disease activity.
• Th17 cells are functionally heterogeneous, producing various cytokines like IL-17, IFN-γ, and GM-CSF, depending on the inflammatory environment.
• Distinct effector phenotypes of human Th17 cells and their correlation with MS disease activity require further investigation.

Purpose of the Study:

• To investigate distinct effector phenotypes of human Th17 cells.
• To correlate these phenotypes with disease activity in multiple sclerosis patients.
• To explore the role of Th17 subpopulations in central nervous system (CNS) infiltration and therapeutic responses.

Main Methods:

• Functional assessment of T helper memory populations (CCR6+CXCR3+, CCR6+CXCR3-) in blood and cerebrospinal fluid (CSF) from MS patients (clinically isolated syndrome, relapsing-remitting MS, end-stage MS) and healthy controls.
• Analysis of cytokine production (IFN-γ, GM-CSF) and very late antigen-4 (VLA-4) expression.
• Ex vivo confirmation of local enrichment using CSF and brain single-cell suspensions.
• Assessment of transmigration across human brain endothelial cells.

Main Results:

• Low frequencies of Th1-like Th17 (CCR6+CXCR3+) effector memory cells in blood correlated with a rapid diagnosis of clinically definite MS.
• Th1-like Th17 cells were abundant in CSF of early MS patients, showing increased IFN-γ and GM-CSF production compared to CD8+ T cells.
• The Th17.1 subpopulation (CCR6+CXCR3+CCR4-) exhibited high VLA-4 expression and selectively accumulated in natalizumab-treated MS patients who remained relapse-free, suggesting CNS infiltration potential.

Conclusions:

• Th1-like Th17 cells, particularly the Th17.1 subpopulation, significantly contribute to MS clinical disease activity.
• These findings support the rationale for earlier and more targeted T cell-based therapies in MS treatment.
• Understanding Th17 heterogeneity is crucial for developing effective MS immunotherapies.