Natural killer (NK) cells play an important role in the innate immune defence against tumors and viruses. In contrast to T and B cells, NK cells do not express clonally distributed antigen-specific receptors. Rather their reactivity is controlled by an interplay of a multitude of inhibitory and activating receptors. Most inhibitory receptors are specific for MHC class I molecules and thus suppress NK cell reactivity against cells properly expressing MHC class I molecules. Whereas function, specificity, and structures of many inhibitory receptors has been described, activating NK cell receptors, their specificity and function are less understood.
Among these activating NK cell receptors, the C-type lectin-like, homodimeric NKG2D receptor has gained considerable interest. In humans, NKG2D is present on most NK cells, but also on CD8abT cells, andgdT cells and associates with the adaptor protein DAP10. DAP10 mediates costimulation of CD8 T cells and triggers cytotoxicity by NK cells, whereas signal transduction via DAP12 augments cytotoxicity and is strictly required for activation of cytokine release. A peculiarity of NKG2D resides in its interaction with a multitude of MHC class I-related ligands that are inducibly expressed in association with cell stress, infection or malignant transformation. In humans, the MHC-encoded MIC molecules (MICA and MICB) and six members of the ULBP family (ULBP1-6) ligate NKG2D and consequently trigger NK cells. MIC molecules are expressed by tumors, and are inducible by cell stress and by infection with HCMV, Mycobacterium tuberculosis, and E. coli. In mice, a strong stimulation of tumor immunity by tumor cells expressing NKG2D-ligands has been demonstrated. Tumor cells release soluble MIC molecules by proteolytic shedding and this may contribute to the failure of tumor surveillance by the NKG2D system in humans. To define the biological function of the NKG2D/NKG2DL-system in vivo, a model of “induced-self” recognition was put forward postulating that NKG2DL may act as danger signals marking dysfunctional cells for destruction by cytotoxic lymphocytes including Natural Killer (NK) cells, CD8abT cells andgdT cells.
NKG2D is encoded in the Natural Killer Gene Complex (NKC) together with many other C-type lectin-like receptors expressed by NK cells, T cells and myeloid cells. Many of these receptors are orphan receptors with unknown ligands and unclear functional significance. We previously showed that the NKC-encoded NK receptor NKp80 ligates the adjacently encoded AICL protein establishing an activating molecular axis between NK cells and myeloid cells (Welte et al., Nat. Immunol. Dec 2006).
A. Molecular basis and clinical relevance of NKG2D-mediated tumor immunosurveillance
1. Expression and regulation of expression of NKG2D-ligands
2. Soluble NKG2D-Ligands: Mechanism of release and diagnostic relevance.
3. NKG2D-Immunosurveillance in vivo
B. Molecular basis of NK cell recognition of virus-infected cells
1. NKG2DL expression by virus-infected cells and consequences for NK cell recognition
2. HCMV-encoded evasins of NK cell recognition
C. NKC-encoded C-type lectin-like receptors of the NKRP1 and CLEC2 families
1. Ligand identification of NKC-encoded orphan NK receptors (e.g. NKp80, NKp65)
2. Analysis of structure, expression and function of these NK receptors and their ligands