Distinct Effector Programs of Brain-Homing CD8⁺ T Cells in Multiple Sclerosis

Area of Science:

• Immunology
• Neuroscience
• T cell biology

Background:

• CD8+ T cell effector functions are regulated by transcription factors RUNX3, EOMES, and T-bet.
• The role of these factors in defining brain-homing CD8+ memory T cells in multiple sclerosis (MS) is not fully understood.

Purpose of the Study:

• To investigate the impact of RUNX3, EOMES, and T-bet expression on CD8+ T cell phenotypes in MS.
• To identify specific CD8+ T cell subsets that home to the brain in MS patients.

Main Methods:

• Analysis of blood, cerebrospinal fluid (CSF), and brain tissues from MS patients and healthy controls.
• Flow cytometry to assess transcription factor expression (RUNX3, EOMES, T-bet) and cell surface markers (CCR5, granzyme K, CD20, CD69).
• Correlation analysis with MS risk single nucleotide polymorphism (SNP) rs6672420.

Main Results:

• Treatment-naïve MS patients showed reduced frequencies of RUNX3+ and EOMES+ CD8+ memory T cells in blood compared to controls.
• These reductions were not observed in MS patients treated with natalizumab.
• Loss of T-bet in RUNX3+ cells was associated with the MS risk SNP rs6672420.
• RUNX3+EOMES+T-bet- CD8+ memory T cells, expressing brain residency markers, were enriched in MS CSF.
• In MS brain tissue, T-bet re-emerged in specific CD8+ T cell subsets, with increased granzyme K and B production.

Conclusions:

• Coexpression of RUNX3 and EOMES, independent of T-bet, identifies CD8+ memory T cells with a brain-residency phenotype.
• These cells are predisposed to enter the central nervous system (CNS) in MS.
• Understanding these T cell subsets may offer new therapeutic targets for MS.