Trends in Immunology
ReviewNKG2D ligands: key targets of the immune response
Section snippets
Structure and function of NKG2D ligands
Natural killer (NK) cell function is regulated by a delicate balance of signals initiated from a variety of activating and inhibitory receptors. NKG2D is an activating receptor expressed by NK cells, CD8+ TCR (T cell receptor) αβ and γδT cells 1, 2, 3, 4. In NK cells, NKG2D serves as a primary activation receptor, which is by itself able to trigger cytotoxicity. In CD8 T cells, NKG2D acts as a co-stimulatory receptor of TCR-activated cells. However, it has been also reported that, depending on
Transcriptional regulation of NKG2DL expression
The ligands of NKG2D are frequently overexpressed in tumors from multiple origins 6, 12, 13, 18, 21, 22, 23, 24, 25, 26, 27. The central role of tumor suppressor and oncogenes in the pathogenesis of cancer suggests that these might be the main candidates for the induction of NKG2DL expression in transformed cells. In chronic myeloid leukemia, the BCR/ABL (breakpoint cluster region/abelson) fusion oncoprotein induces the expression of MICA on the surface of leukemic cells, but it is absent on
Stimuli involved in the upregulation of NKG2D ligands
The first insight into the regulation of NKG2DL was the finding that MICA/B promoters resembled those of heat shock protein 70 (HSP70) and that heat shock induces MICA expression [18] (Table 1). This finding provides the first evidence that NKG2D is able to detect cellular stress, which is a status frequently associated with cancer and infection. Similarly, NKG2DL expression is upregulated in response to oxidative stress 42, 43 and is also induced in nontumor cell lines by genotoxic stress and
Diversity of NKG2D ligands
A characteristic of the NKG2D system is that there are multiple ligands for this receptor [56]. A key question regarding NKG2D is why such a diversity of ligands exists. Common sense suggests that the redundancy of NKG2DLs may reflect a mechanism to counter immune evasion by pathogens. In this regard, human cytomegalovirus (HCMV) has evolved proteins such as UL16 that cause the intracellular retention of MICB, ULBP1 and ULBP2, but not MICA and ULBP3 57, 58, 59 and UL142, which is able to retain
Impairment of NKG2DL function in cancer
The immune system is able to kill cancer cells. However, if the tumor is not completely eliminated, the immune system ends up ‘sculpting’ or ‘editing’ the phenotype of the tumor, resulting in elimination of the most immunogenic cancer cells and favoring the development of nonimmunogenic tumors [39]. Therefore, the first observation that MICA is broadly expressed on multiple primary tumors was paradoxical [12]. Nevertheless, a systemically diminished NKG2D expression on T and NK cells was
Concluding remarks
Although MHC molecules present peptides to T cells, NKG2DLs are upregulated in response to cellular stress, which is usually caused by infection or cellular transformation. To analyse the mechanisms and pathways involved in the regulation of these genes, the promoter architecture and transcriptional regulation of several ligands of NKG2D have been recently analysed. Unexpectedly, these genes are essentially regulated by ubiquitous transcription factors. However, the current information suggests
Acknowledgements
This work was supported by the Spanish grants of Fondo de Investigaciones Sanitarias PI-06/0841, FICYT PC-06/010 and “Fundación Mútua Madrileña 2007-2009” and Red de Investigación Renal REDinREN (RD06/0016). A.L.S. holds a predoctoral fellowship from FICYT of Asturias (ref. BP06-99).
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