T HELPER 22 CELLS INCREASE IN MULTIPLE SCELROSIS PATIENTS: PHENOTYPICAL AND FUNCTIONAL CHARACTERIZATION

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. We have shown that while T helper (Th)17 cells were barely detectable in the peripheral blood (PBMC) from healthy subjects and patients with inactive MS, they were increased strikingly in patients with clinical signs of an MS exacerbation. Longitudinal analysis showed that the increase in Th17 cells was always associated with the shift from inactive to active disease in relapsing-remitting (RR) MS. In this study, we focused our attention on IL-22, a pro-inflammatory cytokine initially related to Th17, but recently associated to a new Th subset. We quantified the frequency of ex vivo CD4 IL-22-producing T cells in PBMC and in some cerebrospinal fluid (CSF) of untreated patients affected by RRMS. We found a significant increased number of IL-22-producing CD4+ cells in RRMS patients with respect of healthy subject. The frequency of these cells enlarged in the CSF, as well as IL-17-producing CD4+ cells. Longitudinal analysis showed that, in the PBMC, IL-22-producing CD4+ cells increased mostly during the relapses and were specific for the auto-antigen myelin basic protein (MBP). To further characterize Th22 cells in RRMS, we analyzed the expression of CCR6, CCR4, CCR10, CD161, IL23R, IL7R and IFNaR1 on Th22 cells in comparison with Th17 cells. Higher expression of CCR6, but not CCR4 and CCR10, on Th22 and Th17 cells in active patients could promote Th22/Th17 invasion of the central nervous system by binding the specific receptors expressed on brain blood barrier epithelial cells. Of interest, Th22 cells express lower level of IFNaR1 compared to Th17 cells, and peripheral Th22 frequency in patients treated with IFNβ is similar to that untreated. Altogether these data suggest that Th22 cells may constitute a new relevant pathogenic subset in multiple sclerosis that display refractoriness to IFNβ inhibitory effects.