**3.2 RAGE and NK cells**

Natural Killer (NK) cells are cytotoxic innate lymphocytes that bridge innate and adaptive immune systems. NK cells' importance is firmly cemented in the field of cancer immunology due to their unique ability to recognize and destroy tumors and virus infected cells. Their killing capacity is driven by the activating and inhibitory receptor-ligand interactions as well as cytolytic granules containing perforin and Granzyme B similar to the CD8<sup>+</sup> T cells. Some important lectin-like activating receptors include NKG2D and KLRG1 whilst inhibitory include NKG2A and KIRs in humans and Ly49 in mice [47]. Unsurprisingly, NK cells are coming into focus in the context of T1DM as an important effector population for the disease pathogenesis. Their interaction with and ability to suppress other effector cells such as CD8+ T cells is of vital importance, particularly in the setting of autoimmunity [48].

During early human studies it was shown that proportion of NK cells was significantly lower in the peripheral blood of individuals with T1DM compared to controls. This was further linked to reduced lytic and cytotoxic capacity of NK cells and more frequent occurrence of tumors [49–51]. The dysregulation in NKG2D signaling as well as reduction in NK cell proportion was suggested to be a contributing factor to the development of T1DM [52].

HMGB1 a known RAGE ligand plays an important role in NK cell killing ability upon activation. HMGB1 released from NK cells' cytotoxic granules is very effective against oxygen-dependent cancer cells whilst those cells with anaerobic energy metabolism were resistant to HMGB1 mediated killing [53]. These observations are of importance with respect to pancreatic inflammation and associated pathologies. Narumi et al. proposed an NK cell-RAGE dependent suppression mechanism of S100A8/A9 expressing tumors It was proposed that NK cells express RAGE but not TLR4 which is also known to bind S100 family of proteins [54]. The ligation of S100A8/A9 to RAGE led to activation of NK cells, increasing their cytotoxic ability evidenced by elevated IFN-γ production, increased NKG2D activating receptor activity and amelioration of tumor growth. RAGE blockade reversed these effects, highlighting the importance of RAGE-S100 axis for suppression of tumor growth and NK cell cytotoxic ability [55]. Whilst there is as yet no direct evidence linking T1DM, NK cells and RAGE, the clear involvement of RAGE axis and NK cells in T1DM and other autoimmune and proinflammatory disorders warrants future investigation.
