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Page 282 Cencioni. Neuroimmunol Neuroinflammation 2020;7:277-90 I http://dx.doi.org/10.20517/2347-8659.2020.18

of activated glutamic acid decarboxylase (GAD)-reactive cells [55-59] . In addition, despite CTLA-4 blockage
showing a negative regulation of autoimmune diabetes only in early stages of the life, the PD1-PDL-1
pathway regulated autoreactive T cells throughout the life span of the animal and appeared to be critical
[59]
for progression of autoimmune diabetes . Moreover, polymorphisms that reduce the function of PD-1
[60]
are associated with human TID . PD-1 function was also investigated by using a model that mimics the
naïve pre-immune repertoire. Fewer islet specific BDC2.5 transgenic naïve CD4 T cells were transferred
[61]
into prediabetic NOD mice . BDC2.5 CD4 T cells accumulated in the pancreas surrounding the islet
(peri-insulitis) . When BDC2.5 naïve T cells were preactivated in vitro and then transferred into NOD
[61]
mice, the majority of them accumulated in the pancreas but within the islet (insulitis), developing severer
[61]
TID . The majority of BDC2.5 cells differentiate in IFNg-producing cells. Anti-PDL-1 administration
[61]
caused a conversion from peri-insulitis to destructive insulitis . PD-1 on BDC2.5 naïve T cells regulate
proliferation, C-X-C Motif Chemokine Receptor 3 (CXCR3) expression, infiltration of the pancreas, and
release of inflammatory cytokines IFNg, TNFa and IL-2. Moreover, PD-1 but not PDL-1 expressed by
[61]
BDC2.5 cells is required to suppress proliferation and infiltration of the pancreas .

A fusion protein containing a single-chain variable fragment (scFv) of PD-1 antibody (aPD-1), an albumin-
+
[62]
binding protein and Pseudomonas aeruginosa exotoxin A was used to select and kill PD-1 cells . The
+
treatment was tried first in animal model of TID. Depletion of PD-1 cells inhibited the development
+
of TID in NOD mice, reducing the pancreatic infiltration of PD-1 cells as compared with the controls.
Contrarily, anti-PD-1 was observed to induce a TID progression in NOD mice, suggesting that PD-1
blocking restores the proliferation and effector function of autoreactive cells. The TID progression was
reduced in mice pre-treated with PD-1 depletion before PD-1 blocking, confirming that PD1 is expressed
[62]
in autoreactive cells .
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Disease genetic
and cellular studies sustain that autoreactive T cells are responsible for CNS damage [63,64] . Post-mortem
studies showed that T and B cells infiltrate the CNS and, in the long term, develop lymphoid follicles
with a functional germinal centre in the meninges and this meningeal inflammation causes white matter
[65]
demyelination . Further investigations demonstrated that inflammatory cytokines and molecules involved
in T and B cell development and lymphoid-neogenesis increased in the cerebrospinal fluid (CSF) from
post-mortem MS cases with a high level of meningeal inflammation and Gray matter demyelination, as
[67]
well as in the CSF of patients with MS and Gray matter damage at diagnosis . Moreover, infiltration of
[66]
[68]
T cells enriched the brain lesions and T- and B-depleted therapies reduced activity and progression in
MS .
[69]
IFNg and IL-17-producing CD4 T cells have been defined as the effector populations driving CNS damage.
Adoptive transfer of Th1 cells inducing experimental autoimmune encephalomyelitis (EAE) and the
cytokine profile of cells isolated from the CNS of mice with acute EAE have shown that Th1 cytokines
+
are released from infiltrating CD4 T cells and TNFa is predominantly transcribed by macrophages and
microglia [70-72] . T-bet is the transcription factor regulating Th1 development and IFNg production, and it
is induced by interferon g transducer and activator of transcription (STAT)-1 signalling pathway during
T-cell activation. The role of Th1 in inducing EAE was confirmed in STAT-4 and STAT-6 deficient mice.
-/-
STAT-4 pathway controls the Th1 differentiation and STAT-4 mice showed resistance to the development
of AEA. Mice deficient in STAT-6, which regulates the differentiation of Th2 cells, develop severer AEA
[73]
+
and have more Th1 phenotype . The IFNg-producing CD4 T cells generate in the cervical lymph nodes
[74]
and Th1 migration happens 24 h before the onset of neurological signs of EAE . Although Th1 cells
contribute to EAE, IFNg knockdown mice are predisposed to develop EAE and infiltrates of lymphocytes,
macrophages and granulocytes were detected in the CNS [75-77] . The results from IFNg knockdown and
STAT-1 deficient mice established the contribution of other effector cells to the disease pathogenesis.