Type I TNFR family

TNFa, lymphotoxin

Activation, apoptosis

CD95 (Fas)

Type I TNFR family

CD95L (FasL)

Activation, apoptosis

IgSF, Immunoglobulin superfamily; VCAM, vascular cellular adhesion molecule; ICAM, intercellular adhesion molecule; CR, complement receptor: FN, fibronectin; VTR, vitronectin.

"The list of activating or cytokine receptors expressed on NK cells is not all inclusive

IgSF, Immunoglobulin superfamily; VCAM, vascular cellular adhesion molecule; ICAM, intercellular adhesion molecule; CR, complement receptor: FN, fibronectin; VTR, vitronectin.

"The list of activating or cytokine receptors expressed on NK cells is not all inclusive get cells bearing Ig results in antibody-dependent cellular cytotoxicity (ADCC), proliferation and cytokine production by NK cells. Engagement of the CD 16 complex, consisting of CD 16 and associated dimers of CD3£-CD3£; FceRry-CD3£; FceRI-y-FceRI-y on NK cells leads to activation of the intracellular signaling pathway similar to that induced by TCR-CD3£ activation in T cells. Importantly, the participation of antibody in this type of signaling confers specificity upon those NK cells that express FcyRIII. Some human NK cells also express FcyRIIc (CD32, isoform c), and it appears to be a signaling molecule on NK cells. The third type of FcR recently described, FcpR (receptor for IgM), is a triggering molecule expressed on the majority of NK cells. However, its cross-linking with IgM at physiological concentrations results in negative regulation of several NK cell functions, including cytotoxicity. A broad range of CAMs are detectable on NK cells (Table 1) and participate in signal transduction and activation of NK cells. For example, VLA-4 and VLA-5 (receptors for fibronectin) and VLA-6 (receptor for laminin) facilitate binding of NK cells to the relevant substrates and induce NK cell activation. Costimulatory molecules, such as CD2, CD69 or NKR-P1 may also be involved in triggering of cytolytic function in NK cells. Monoclonal antibodies to these various surface molecules, acting as agonists, can initiate antibody redirected lysis of FcR-bearing targets (Figure Id). Overall, it appears that cooperative engagement of several activating or costimulatory receptors interacting with their respective ligands on target cells is sufficient to induce a lytic pathway in NK cells.

Inhibitory receptors on NK cells

A novel class of receptors recognizing class I MHC molecules and capable of inhibiting lysis has been recently described on NK cells (Table 2). In rodents, the Ly-49 family of receptors expressed on NK cells includes at least eight distinct type II disulfide-linked homodimers of C-type lectins which bind H-2 class I ligands on target cells and inhibit NK cell-mediated lysis. In humans, a distinct family of killer cell inhibitory receptors (KIRs), which are type I transmembrane proteins of the Ig superfamily, has been identified. These receptors bind class 1 HLA molecules on target cells, and their ligation induces a negative signal and abrogation of the lytic process (Figure la). This function is mediated by phosphorylation of cytoplasmic tyrosines, which recruit the protein tyrosine phosphatase SHP-1. The absence


HLA molecule —• Decreased or absent HLA

Ags recognized by the Ab + positive signal negative signal

Figure 1 Interactions of NK cells with cellular targets do not result in lysis if the target cell expresses class I HLA molecules recognized by the HLA-specific receptor on the NK cell. Positive signals induced by binding of NKARs to their ligands on the target are superseded by negative signals transduced via KIRs, which bind to HLA alleles recognized on the target (A). If, however, expression of the HLA-alleles recognized by KIRs on the target is decreased or the target lacks these alleles, negative signals cannot be generated, and the target cell is lysed by the NK cells receiving positive signals via NKARs (B). In the presence of any antibody decorating the NK cell through Fc-yRlll and recognizing an antigen on the target, antibody-dependent cellular cytotoxicity (ADCC) leads to target cell lysis (C). If, however, the antibody decorates the target cell and also recognizes a signaling molecule on the NK cell, Ab-mediated redirected lysis occurs (D).

Table 2 Inhibitory receptors of NK cells (KIRs)a


Surface antigen structure


Ly-40 family p58

p70 (NKBI) p140

CD94/kp43 (NKG2-A)

Type II lectin-like Type I IgSF (2D) Type I IgSF (3D) Type I IgSF (3D) lg-like protein (3D) Type II lectin-like

Class I MHC alleles (murine) HLA-C alleles HLA-BW4 alleles H LA-A alleles

Class I alleles

Effect on NK killing

Inhibition Inhibition Inhibition Inhibition


D, lg domain; IgSF, immunoglobulin superfamily.

"Inhibitory receptors on NK cells contain xY/xxL sequences in the cytoplasmic tail, which are termed immunoreceptor tyrosine-based inhibiting motifs (ITIM) and which are necessary for inhibitory function.

of class I HLA molecules or their decreased expression on target cells leads to NK cell-mediated lysis of the target (Figure lb). KIRs belong to a large and diverse family of receptors, which appear to be distributed in different combinations on distinct NK cell clones and NK cell subsets. This family also contains MHC receptors which activate rather than inhibit NK cytotoxicity, e.g. the p50.3 receptor involved in HLA-C recognition in humans (Table 1). Furthermore, MHC receptors have been detected not only on NK cells but also on subsets of T cells. The presence of both inhibitory and stimulatory MHC receptors on the same NK or T cell indicates that immune responses are regulated by maintaining a delicate balance between positive and negative signals induced upon recognition of MHC alleles on target cells.

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