Mapping CD4+ T cell diversity in CSF to identify endophenotypes of multiple sclerosis

Area of Science:

• Neuroimmunology
• Cellular Immunology
• Translational Medicine

Background:

• Multiple sclerosis (MS) is a chronic, heterogeneous inflammatory disease of the central nervous system (CNS).
• Early prognostic markers are crucial for patient stratification, especially for those at high risk of progressive disease.
• Cerebrospinal fluid (CSF) analysis offers potential for improved diagnostic resolution in MS.

Purpose of the Study:

• To investigate if spectral flow cytometry of CSF cells can identify pathogenic CD4+ T cell subsets in MS.
• To determine phase-specific CD4+ T cell markers indicative of disease progression in a murine model (EAE) and translate findings to human MS.

Main Methods:

• Utilized a two-step approach combining transcriptomic data from human MS and single-cell RNA sequencing (scRNA-seq) in experimental autoimmune encephalomyelitis (EAE).
• Designed a marker panel based on identified chronic phase markers in EAE.
• Applied spectral flow cytometry to an independent MS cohort using CSF cells.

Main Results:

• Identified chronic phase markers in EAE, including those associated with memory T cells, pro-survival signaling, and tissue residency (e.g., Il7r, Ramp3, Itgb1, Dnaja1, Hsph1, Jun/AP-1, CXCR6, CD69, Bhlhe40).
• Found enrichment of these phase-specific markers in CSF cells from MS patients.
• Spectral flow cytometry revealed distinct memory and effector T cell subsets in MS CSF, indicating unique cellular signatures.

Conclusions:

• CD4+ T cells exhibit dynamic changes and heterogeneity in MS, detectable by spectral flow cytometry.
• These findings enhance the diagnostic resolution of CSF cells in MS.
• The identified T cell signatures can inform more precise therapeutic strategies for multiple sclerosis.