Natural Killer Cell Receptor: C-Type Lectin Receptors
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P223
2025-12-10
25
The CTLRs, located on human chromosome 12p12.3, share a common subunit (CD94) covalently bonded to one of four closely related gene products of the NKG2 family. CTLRs promote a second type of NK cell receptor–mediated killing and include NKG2A (and splice variant B), NKG2C, NKG2E (and splice variant H), and NKG2F. NKG2D, which does not bind CD94 and shares little sequence homology to other NKG2 proteins, is discussed below. The CTLRs expressed on NK cells and cytotoxic T lymphocytes are activating except for CD94/NKG2A which is inhibitory. CD94/NKG2A specifically recognizes the non-classical HLA-E class I molecule. HLA E*0101 and HLA-E*0103 are the only two alleles present worldwide. Tumor cells may exhibit upregulation of HLA-E expression, presumably to avoid NK cell cytotoxicity. High-level expression of HLA-E is associated with poor prognosis in several cancers, and blockade of this ligand-receptor interaction can enhance NK cell anti-tumor activity. HLA-E is able to present leader peptides from other HLA molecules which provides an additional mechanism for NK cells to sense the expression of class I MHC molecules on the cell surface. As is seen with KIR interactions, binding of CD94/NKG2A to HLA-E is more avid than binding of activating CTLRs to other epitopes.
NKG2D is a CTLR; however, it does not associate with CD94 and has limited sequence homology with other members of the NKG2 family. NKG2D exists as a homodimer and does not have intrinsic signaling capacity, but instead interacts with the DAP10 adapter molecule which is able to provide signals that recruit the p85 subunit of phosphatidylinositol 3-kinase and a complex of GRB2 and VAV1. This signal transduction arrangement effectively isolates the NKG2D signal from inhibitory signals that can suppress NK cell activation by other CTLRs. NKG2D is constitutively expressed at high levels on all NK cells, as well as on γδ T cells and CD8+ T cells. NKG2D binds to two different classes of MHC-I-like ligands whose expression is markedly induced by cellular stress, such as viral infection or malignant transformation. This binding event then leads to enhanced degranulation/cytotoxicity and production of IFN-γ. The ligands for NKG2D include the highly polymorphic MHC class I chain–related proteins MICA and MICB and 6 members of the UL16 binding proteins (ULBPs). MICA and MICB expression is under the control of promoter elements similar to those that regulate the heat shock proteins which are upregulated in malignant cells and also those infected with cytomegalovirus (CMV). UL16 is a virus-encoded type I transmembrane protein expressed in the setting of CMV infection that binds to ULBP-1 and ULBP-2 and allows the virus infected cell to escape NK cell surveillance. Similarly some human tumors downregulate expression of NKG2D ligands or release soluble forms of MICA as a mechanism of immune escape from NK cells. Conversely, MICA expression by normal monocytes could provide a stimulus to NK cell activity against antibody-coated tumor cells.
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