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Page 278 Cencioni. Neuroimmunol Neuroinflammation 2020;7:277-90 I http://dx.doi.org/10.20517/2347-8659.2020.18

T-CELL EXHAUSTION
The word “exhaustion” originates from the Latin “exaurire” and was used for the first time to explain a
mechanism for silencing antiviral T-cell response during a Lymphocytic Choriomeningitis Virus infection
[1]
(LCMV) . Antigen-specific CD8 T cells remove viral infection by killing infected cells and the production
of antiviral cytokines such as interferon gamma (IFNg). The damping of immune response in LCMV
was associated with two mechanisms silencing the CD8 Cytotoxic T Lymphocytes (CTLs) response: the
depletion of nucleoprotein-specific CD8 T cells and the persistence of exhausted glycoprotein-specific
[1]
CD8 T cells unable to kill virus-infected cells and release antiviral cytokines . Further investigations
showed that the exhaustion process suppresses the CD8 antiviral activity by the hierarchical loss of T cell
[2]
function . Proliferation, release of IL-2 and cytolysis were lost at an early stage of exhaustion, followed
by tumor necrosis factor alpha (TNFa) production and, at the severe late stage, IFNg production. CD4 T
helper cells (Th cells) drive the fate of CD8 T-cell responses in chronic viral infections. Mice with transient
depletion of CD4 T cells before infection with chronic strains of LCMV develop CD8 T-cell exhaustion
[3]
and high viral load compared with non-treated mice . Th cells are necessary for the generation of stable
[4-6]
and functional CD8 memory cells . During a chronic infection, CD8 T cells develop an exhaustion
[7]
phenotype that produces a state of immunosuppression in the absence of CD4 T cells . The exhaustion
process induces low levels of Th cells [8-10] and affects CD4 T cell functions with loss of proliferation and IL-2
[11]
and TNFa production . Moreover, CD8 T cell and B cell response was restored when functional LCMV-
specific CD4 T cells were transfected in LCMV chronically infected mice. PD-1 expression increased in
LCMV-specific CD4 T cells by two weeks after transfer in chronically infected mice and programmed death
1 (PD-1) blockage improved the CD4 T-cell activity [12,13] . In addition, the rescue of CD8 T cell function in
terms of proliferation and cytokine release was greater in mice receiving the combination of PD-1 blockade
and Th cells compared with the mice receiving either treatment alone .
[12]

INHIBITORY CHECKPOINT PATHWAYS
Cytotoxic T Lymphocytes A-4 (CTLA-4), PD-1 and programmed death ligand 1 (PDL-1) are the first
inhibitory checkpoint receptors to be discovered and targeted in cancer immunotherapy and chronic
viral infection. The amplitude of T-cell response depends on the activation of co-stimulatory (CD28)
or inhibitory receptors after the engagement of T-cell receptor (TCR) with the cognate-peptide-major
histocompatibility complex. Co-inhibitory receptors show distinct patterns of expression and different
mechanisms of action and signalling.

The knockout CTLA-4 mice has shown a lethal hyperactivation phenotype, confirming that CTLA-4 is a
vital inhibitor checkpoint of the immune system. After TCR activation, CTLA-4 upregulates in the CD4
T cells and competes with the co-stimulatory receptor CD28 for its ligands CD80 and CD86, for which
CTLA-4 has more binding affinity. The link of CTLA-4 to CD80 and CD86 inhibits T-cell activation.
Because antigen-presenting cells and dendritic cells express CD80 and CD86, the suppression of anti-
tumour immunity by CTLA-4 is thought to occur in the secondary lymphoid organs as well as in the
tumour microenvironment.

PD-1 is an inhibitory receptor that belongs to the CD28 family. The receptor has been detected on activated
T lymphocytes, B lymphocytes, dendritic cells, macrophages and natural killer cells after a transcriptional
[14]
activation . PDL-1 is the ligand of PD-1, belongs to B7 family and is present on B lymphocytes, antigen-
presenting cells (APC) and tissue cells, including several types of cancer. PD-1 engagement activates the
inhibitory phosphatase PP2A and SHP-2 by immune receptor tyrosine inhibitory motif and immune
receptor tyrosine switch motif, inhibits T-cell activation and increases T-cell migration within tissues.

T-cell exhaustion in cancer and infectious diseases. T-cell exhaustion has been described in animal
[15]
[16]
models of polyomavirus and adenovirus , as well as in chronic human infections mediated by human