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Cencioni. Neuroimmunol Neuroinflammation 2020;7:277-90 I http://dx.doi.org/10.20517/2347-8659.2020.18 Page 283

Besides, the discovery of IL-23 rather than IL-12 being crucial for EAE development led to evaluating Th17
cells and their transcriptional factor RORgt in the EAE pathogenesis [78-80] , Moreover, Th1, Th17 and Th9
[82]
were defined to induce EAE with a different disease phenotype [79,81] . In addition to effector cells in EAE ,
the mechanisms of immune regulations, including regulatory B and T cells, and expression of inhibitory
receptors were investigated in EAE. CD4 T cells were observed to protect against spontaneous development
[83]
of CNS autoimmunity in EAE , and CD4 regulatory T cells characterised by high expression of CD25 and
transcription factor FOXp3 isolated from peripheral blood had a reduced effector suppression function in
[84]
patients with MS as compared with healthy donors . A defect in regulatory B cells was also described to
induce EAE and autoimmunity in mice and patients [85,86] .

Single-cell transcriptomics of blood and CSF cells isolated from patients with MS and healthy donors
[87]
revealed that different mechanisms operate in the two compartments . Analysis of the data showed that
[87]
MS affects the cellular composition of the CSF and the transcriptional phenotype of blood cells . Blood
cells exhibited several transcriptional changes, including induction of activation markers (ICOS), cytokine
[87]
receptors (IL17RA) and trafficking molecules (PECAM1/CD31 and ITGA5/a5 integrin) in T cells .

Contrarily, an enrichment of CD4 T cells with T helper 1 and T follicular helper (Tfh) profiles, regulatory T
[87]
cells, myeloid lineage cells and late-stage B lineage cells were detected in the CSF . Furthermore, Tfh cells
expressing PD-1 were observed to correlate with the proportion of plasma cells and showed cytotoxicity
and co-inhibitory function. Follicular T helper (Tfh) cells, a subset of T helper cells, are necessary for B cell
differentiation and antibody production [87,88] . These cells express CXCR5, CD40 ligand and IL-21 as well
as high levels of inducible T-cell constimulator (ICOS) and PD-1. They were described to migrate in the
germinal centre and to activate B cells. An elevated frequency of circulating Tfh and B cells was identified
[88]
in MS patients undergoing relapse and Tfh-like cells upregulated during the course of EAE progression .
In addition, an adoptive cell transfer experiment showed that myelin oligodendrocytes glycoprotein
(MOG)-reactive Tfh-like cells induced a worsening of the disease, delaying the remission of EAE in vivo .
[88]
Despite the use of PD-1 to identify Tfh cells, the role of PD-1 signalling on Tfh cells is only beginning to
be investigated. When PD-1 is engaged by its ligand PDL-1 on follicular B cells, a bystander mechanism
is activated and PD-1-expressing Tfh cells are recruited into a special niche inside the GC, even though
Tfh PD-1 migrates to the follicle outside of the germinal centre . Moreover, both ICOS and PD-1 are
neg
[89]
requested for maintaining the stringency of affinity-based selection between Tfh cells and antigen-specific
[89]
cells .
The transcriptional signature of CD8 T-cell exhaustion predicted better prognosis in multiple autoimmune
[90]
diseases . Transcriptomes of CD4 and CD8 T cells isolated from a group of patients with active
autoimmune diseases were analysed to identify modules of genes with a strong correlation with relapse rate.
Modules corresponding to CD4 T-cell co-stimulation were found to correlate with clinical outcomes. In
detail, CD4 co-stimulatory receptors, CD2, KAT2B and other surrogate markers were described to increase
in MS patients with active autoimmune disease.

The immune regulatory role of PD-1 in MS was suggested by experiments in EAE, a mouse model of
MS [59,91,92] . Mice in which PD-1 was deleted or the PD-1 pathway was inhibited by blocking the link
between PD-1 and its ligand PDL-1 develop a worsening EAE with an increase of infiltrating immune cells,
-/-
-/-
especially CD8 T cells into the CNS [59,92,93] . The deterioration of disease in PD-1 and PDL-1 mice was
related to over production of inflammatory cytokines IFNg, TNFa, IL-6 and IL-17 released by draining
lymph node cells during re-stimulation in vitro with different concentrations of MOG . PDL-1 is rarely
[93]
[94]
expressed in the brains of controls . Contrarily, PDL-1 was detected in the majority of lesions expressed
from astrocytes and microglia/macrophages with low expression of PD-1 on infiltrating T cells in post-
[94]
mortem MS brain tissues . A recent publication shows that the PDL-1 in dendritic cells improves EAE in