S (55). Collectively, the presence of ULBP1 and IL-15 receptor by DC-derived exosomes promoted NK cell activation and proliferation (55). NKG2D ligands on DCs might be essential regulators of T cell function at the same time. ULBP1 expression was observed by DCs in regions of T cell interaction in lymph nodes, suggesting a function for ULBP1 on DCs within the induction or reactivation of T cell responses (56). Zloza et al. located that transgenic expression of RAE-1 on DCs at the time of priming rescued memory recall by CD8+ T cells inside the absence of CD4+ T cells. They discovered that RAE-1 expression by DCs did not impact effector T cell responses, but conferred a high rate of survival of CD4+ T cell-deficient animals in a model of influenza in which viral elimination is ordinarily CD4+ T cell-dependent. In addition, they showed that RAE-1 stimulation rescues HIV-specific CD8+ T cell responses in CD4+ T cell-deficient HIV-positive donors (57). Evidence suggests that NKG2D ligand expression by DCs may well not usually be activating, but can also negatively regulate immune function. Transgenic expression of RAE-1 by DCs causes downregulation of NKG2D on NK cells and impaired NKG2D-dependent NK cell functions, which includes tumor rejection (58). Correlative evidence comes from a study by Fabritius and colleagues who discovered expression of RAE-1 on DCs in the spleen and lymph nodes of C57BL/6 mice and demonstrated that deletion of NKG2D accelerates rejection of cardiac allografts (59). Also, NKG2D ligand expression on DCs infected with an ULBP-expressing cytomegalovirus resulted in decreased MHC class I expression by the DCs (60). This effect is constant withFUNCTiON OF NKG2D LiGAND eXPReSSiON BY MONOCYTeS AND MACROPHAGeSDuring the original characterization of MICA, Zwirner et al. located that MICA protein was expressed by monocytes from a number of donors utilizing Western blot (19). Due to the fact, the expression of NKG2D ligands by monocytes and mAChR1 Agonist Storage & Stability macrophages has been investigated by several groups, with outcomes suggesting two major functions. Among these functions was suggested by Hamerman et al., who showed that toll-like receptor (TLR) signaling via MyD88 in murine macrophages induced RAE-1 and that NK cells cocultured with these RAE-1-expressing macrophages internalized NKG2D from the surface both in vitro and in vivo (40). This suggests that ligand expression by macrophages is involved in communication amongst macrophages and NK cells. This notion is supported by another study displaying that expression of RAE-1 by murine macrophages downregulates NKG2D surface expression by NK cells and inhibits the NK cell response against B16 tumors (41). MICA expression by human monocytes was also shown to enhance NK cell interferon gamma (IFN-) production and antitumor function through an NKG2D-dependent mechanism (42, 43). In addition to communication with, and regulation of, NK cells, it appears that expression of NKG2D ligands also tends to make macrophages susceptible to regulation by direct NKG2Dmediated killing. Autologous killing of macrophages and monocytes by NK cells or NKG2D-expressing CD4+ T cells was shown right after induction of NKG2D ligand expression on monocytes by lipopolysaccharide (LPS) stimulation, in vitro culture with IL-10, or on monocytes from individuals with systemic lupus erythematosus (446). Other observations consist of IL-2 Modulator manufacturer upregulation of NKG2D ligands by human monocytes, too as murine macrophages and microglial cells, in response to GM-CSF along with other myeloid growth facto.
