Patients With Severe Multiple Sclerosis Exhibit Functionally Altered CD8 Regulatory T Cells.

Background And Objectives: Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS. Studies of immune dysfunction in MS have mostly focused on CD4 Tregs, but the role of CD8 Tregs remains largely unexplored. We previously evidenced the suppressive properties of rat and human CD8CD45RC Tregs from healthy individuals, expressing Forkhead box P3 (FOXP3) and acting through interferon-gamma (IFN-γ), transforming growth factor beta (TGFβ), and interleukin-34 (IL-34). secretions to regulate immune responses and control diseases such as transplant rejection. To better understand CD8CD45RC Tregs contribution to MS pathology, we further investigated their phenotype, function, and transcriptome in patients with MS.

Methods: We enrolled adults with relapsing-remitting MS and age-matched and sex-matched healthy volunteers (HVs). CD8 T cells were segregated based on low or lack of expression of CD45RC. First, the frequency in CSF and blood, phenotype, transcriptome, and function of CD8CD45RC and were investigated according to exacerbation status and secondarily, according to clinical severity based on the MS severity score (MSSS) in patients with nonexacerbating MS. We then induced active MOG EAE in C57Bl/6 mice and performed adoptive transfer of fresh and expanded CD8CD45RC Tregs to assess their ability to mitigate neuroinflammation in vivo.

Results: Thirty-one untreated patients with relapsing-remitting MS were compared with 40 age-matched and sex-matched HVs. We demonstrated no difference of CSF CD8CD45RC and CD8CD45RC proportions, but blood CD8CD45RC frequency was lower in patients with MS exacerbation when compared with that in HVs. CD8CD45RC Tregs but not CD8CD45RC showed higher suppressive capacities in vitro in MS patients with exacerbation than in patients without acute inflammatory attack. In vitro functional assays showed a compromised suppression capacity of CD8CD45RC Tregs in patients with nonexacerbating severe MS, defined by the MSSS. We then characterized murine CD8CD45RC Tregs and demonstrated the potential of CD45RC cells to migrate to the CNS and mitigate experimental autoimmune encephalomyelitis in vivo.

Discussion: Altogether, these results suggest a defect in the number and function of CD8CD45RC Tregs during MS relapse and an association of CD8CD45RC Tregs dysfunction with MS severity. Thus, CD8CD45RC T cells might bring new insights into the pathophysiology and new therapeutic approaches of MS.