To unravel how glucocorticoid (GC) insensitivity characterizes brain-homing T cells in multiple sclerosis (MS) patients and whether this can be modulated using other nuclear receptor ligands.

GC treatment dampens acute exacerbations, yet does not prevent recurrent disease in MS. In experimental autoimmune encephalomyelitis, GC efficacy depends on the suppression of brain-homing CD4⁺ T cells. Since GC sensitivity is impaired in MS patients, pathogenic CD4⁺ T-cell subsets likely evade GC-mediated suppression on a long-term basis.

The expression of key determinants of GC sensitivity, multidrug resistance receptor 1 (MDR1) and glucocorticoid receptor (GR), were assessed in Th1 and distinct Th17 subsets from healthy donors. This was compared to brain-homing subsets enriched in the blood of 18 natalizumab-treated MS patients, CSF and blood of 15 treatment-naive early MS patients and 8 neurological controls, as well as brain tissues of 8 end-stage MS patients (FACS and immunohistochemisty). CNS infiltration and GC resistance were studied in vitro using human brain endothelial cell (hBEC) monolayers and proliferation assays.

Th17.1 cells (CCR6⁺CXCR3⁺CCR4^-/dim; IFN-γ^highGM-CSF^highIL-17^low) displayed high MDR1 and low GR expression compared to other pathogenic subsets. MDR1/GR expression ratios were increased in blood Th17.1 cells of natalizumab-treated MS patients. MDR1⁺ Th17.1 cells expressed high levels of pro-inflammatory markers (CCR6, IL-23R, IFN-γ and GM-CSF), preferentially migrated across hBECs, predominated the CSF of CIS and RRMS patients versus controls, and were enriched in MS brain lesions (ex vivo/in situ). GC resistance of Th17.1 cells was abrogated in vitro after the addition of calcitriol with either estrogen or progesterone.  

The selective local enrichment of MDR1⁺ Th17.1 cells in early MS patients supports its further exploration as a biomarker for MS activity. The use of calcitriol and female hormones may be a new strategy to enhance long-term GC efficacy by sensitizing this brain-homing T cell in MS.