Transduction of cytotoxic signals in natural killer cells: a general model of fine tuning between activatory and inhibitory pathways in lymphocytes

Abstract

NK-cells are large granular lymphocytes, which are capable of exerting two major types of effector function, cell cytotoxicity and lymphokine secretion. NK-cells can exert cell cytotoxicity in one of two ways. First, NK-cells are able to recognize and to induce the lysis of antibody-coated target cells during antibody-dependent cell cytotoxicity (ADCC). Second, during natural cytotoxicity NK-cells are also able to recognize and to induce the lysis of a variety of target cells, including primarily virus-infected cells as well as tumor cells. Recently, a novel mechanism has been elucidated which controls NK-cell-activation programs and which is based on the cell surface expression of killer-cell inhibitory receptors (KIR). We will review here the molecular dissection of this inhibitory signalling pathway which utilizes immunoreceptor tyrosine-based inhibition motifs (ITIM) expressed in KIR intracytoplasmic domain. We will also show that this strategy used by NK-cells to regulate their effector functions is a general decision mechanism which exists not only in T- and B-lymphocytes, but also in a variety of other hematopoietic cells.

A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells

“…The 178-aa cytoplasmic tail contains four copies (residues 688-693, 717-722, 769-774, and 799-804) of the sequence motif Ser͞Glu͞Val-Xaa-Tyr-Xaa-Xaa-Val͞Leu, similar to the immunoregulatory tyrosine-based inhibitory motif (ITIM) recently identified in the cytoplasmic domains of the Fc␥RIIB (24-26) and CD22 molecules on B cells (27,28) and the killer inhibitory receptors (KIR) on NK cells (29)(30)(31)(32). This suggests that the PIR-B1 cDNA encodes a receptor molecule that may transduce an inhibitory signal via the interaction of its cytoplasmic ITIM with inositol or protein tyrosine phosphatases (33)(34)(35)(36).…”

“…Receptors with ITIMs, such as the KIR molecules on NK cells and the FC␥RIIB molecules on B cells, deliver an inhibitor signal when they are coligated with ITAM-bearing activation receptor complexes like the B cell antigen receptor. The coligation of the activating and inhibitory types of receptors facilitates the ITIM interaction with inositol or protein tyrosine phosphatases, such as SHIP and SHP-1, thereby blocking elevation of the intracellular calcium pool and effective cell signaling (33)(34)(35)(36).…”

Natural killer cell acceptance of H-2 mismatch bone marrow grafts in transgenic mice expressing HLA-Cw3 specific killer cell inhibitory receptor (CD158b)

“…The identification of KIRs revealed a novel strategy for T and NK cell control that is based on the promiscuous recognition of MHC class I molecules on antigen-presenting cells and target cells (26). Human KIRs belong to two unrelated families of molecules, IgSF (CD158, p70, p140) or dimeric C-type lectins (CD94-NKG2A͞B), whereas only dimeric C-type lectins KIRs (Ly-49) have been described in the mouse (3).…”

Functional expression of CD43 on human natural killer cells

“…[18][19][20]. However, little is known about the participation in the regulation of NK cell activity of surface molecules, which play a critical accessory role in other leukocytes, as is the case of CD43.…”