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.