In addition to secreting soluble factors for the
attraction of immune cells, senescent cells can also become immunogenic through
the up-regulation of ligands that can specifically be recognized by immune
cells. While research into the
recognition and interaction of immune cells with senescent cells is at its
infancy, a number of studies have reported the up-regulation of the Natural
Killer Group 2D (NKG2D) ligands in senescent cells that can be recognized by
receptors on Natural Killer (NK) cells and CD8+ T-cells. Since NKG2D ligands are not widely expressed
on healthy cells, this would allow for specific recognition, interaction and
elimination of senescent cells by immune cells.
As with the senescent secretome, this response is likely not exclusive
to cell senescence as the same mechanism functions in immunosurveillance of
tumour cells (López-Soto et al. 2014). The human NKG2D ligands primarily consist of
MICA, MICB, ULBP1, ULBP2, ULBP3, ULBP4, ULBP5 and ULBP6. The transcriptional up-regulation of MICA and
ULBP2 during cell senescence have been reported in senescent activated hepatic
stellate cells, replicative senescent fibroblasts and HUVECs, etoposide-induced
senescent fibroblasts, fusion-induced senescent fibroblasts and
chemotherapy-induced senescent multiple myeloma cells (Krizhanovsky, et al. 2008, Kim
et al. 2008 Chuprin et al. 2013, Soriani et al. 2014, Lackner et al, 2014). In addition to MICA and ULBP2, microarray
analysis of replicative senescent fibroblasts demonstrated an increase in the
expression of ULBP1 (2.75 fold) compared to growing cells, in addition to the
up-regulation of HLA-E (2 fold) (Lackner et
al. 2014). HLA-E is a non-classical
MHC class I molecule that plays a role in cell recognition by NK cells. However,
replicative senescent vascular smooth muscle cells do not appear to up-regulate
MICA, ULBP2 or ULBP1, at least not greater than 2 fold as assessed by microarray
analysis (Burton et al. 2009). Therefore, it should not be assumed that all
senescent cell types up regulate NKG2D ligands and this should be evaluated in
underexplored senescent cell types. Mechanisms involved in the interaction of
senescent cells with T-cells is less understood, but it appears that major
histocompatibility complex class II (MHCII) expression is required for killing
of pre-malignant senescent hepatocytes by T-cells (Kang et al. 2011). Mice with
liver specific MHCII deficiency resulted in impaired immunosurveillance of
senescent cells.
At the mechanistic level, little
is currently known about the regulation of NKG2D ligand expression in senescent
cells. Nonetheless, some extrapolation
from others models is possible. For
example, MICA and MICB have been reported to be regulated by endogenous miRNAs
in tumours and as a result of infection with cytomegalovirus (Stern-Ginossar et al. 2008). Since miRNAs appear to play a role in
regulating cellular senescence (Feliciano et
al. 2011, Liu et al. 2012
Benhamad et al. 2012) and their
expression is altered in response to DNA damage (Dolezalova et al. 2012, Wang and Taniguchi, 2013), it
is possible that changes in miRNA expression also regulate the expression of
immune ligands in senescent cells.
Soriani et
al demonstrated that the up-regulation of MICA in senescent multiple
myeloma cells was dependent upon the DDR (Soriani
et al. 2014). In other systems, NKG2D ligands have also
been shown to be up-regulated in response to DNA damage and Ras activation via
ATM and ATR (Gasser et al. 2005,
Cerboni et al. 2014). Inhibition of the ATM or ATR pathways
prevented the up-regulation of immune ligands.
It is also possible that the up-regulation of
immune ligands on senescent cells is mediated via the secretory response. In addition to activating and attracting
immune cells, the senescent secretome may serve to up-regulate immune ligands in
an autocrine or paracrine manner. It has
been shown for example, that TNFα can
up-regulate MICA on human endothelial cells and that the addition of exogenous
MICA seems to induce senescence in HUVECs (Lin et al. 2011), but the extent to which this occurs under more
physiologically reflective situations remains unclear.
Immune ligands can also be up-regulated in
response to various other forms of cell stress such as heat shock, metabolic
stress and endoplasmic reticulum (ER) stress (Cerwenka, 2009, Valés-Gómez et al. 2008). Thus, as with the secretory response, mechanisms
exists that can up-regulate immune ligands independent of DNA damage. Given that this is an important aspect of
senescent cell clearance and the number of cell types in which the up-regulation
of immune ligands has been shown is limited, a more detailed study of this
aspect of immunogenic conversion seems warranted.
While senescent cells are likely eliminated by
the immune system during normal physiological processes, it has been speculated
that the accumulation of senescent cells with age could be due to inefficient
elimination by an ageing immune system (Burton, 2009). In fact, immune cells may themselves undergo
cellular senescence, a process that requires further investigations (Effros et al. 2005, Rajagopalan et al. 2012). As such, induction of cell
senescence in immune cells may represent one aspect of immunosenescence, the
gradual deterioration of the immune system, which consequently leads to
impaired immunosurveillance of non-immune senescent cells. It can be speculated that impaired
immunosurveillance may result from altered expression of surface receptors on
immune cells that impair recognition and interaction with target senescent
cells (and cancer cells). In addition,
it is possible that aged or senescent immune cells do not respond as efficiently
to chemoattractants secreted by senescent cells. In order to understand the mechanisms
associated with age-related changes resulting in impaired immunosurveillance of
senescent cells, we must first fully understand the normal processes governing
immune clearance of senescent cells.
However, evaluating the hypothesis that aged or senescent immune cells display
a reduced capacity to target senescent cells and the physiological impact of
this decline can still be assessed. If
this were indeed found to be the case, the rejuvenation of an ageing immune
system would represent an attractive approach for promoting health span.
