Identification of human NK cells that are deficient for signaling adaptor FcRγ and specialized for antibody-dependent immune functions

Abstract

NK cells respond to tumor and virus-infected cells directly through several activation receptors, including natural cytotoxicity receptors, or indirectly through the activating Fc receptor CD16 for antibody-coated cells. Triggering of NK-cell effector functions through these receptors depends on physically associated transmembrane signaling adaptors, such as FcRγ (also known as FcεRIγ) and CD3ζ, both of which have been traditionally believed to be expressed by all mature NK cells. However, we have identified a distinct subset of human NK cells that are deficient for FcRγ expression but express normal levels of CD3ζ. FcRγ-deficient NK cells were readily detectable in about one-third of the healthy individuals examined. The deficiency was confined to the CD56(dim) population and was due to low FcRγ mRNA. FcRγ-deficient NK cells displayed dramatically reduced expression of the natural cytotoxicity receptors NKp46 and NKp30 but still expressed substantial levels of CD16. Compared to FcRγ-expressing NK cells, FcRγ-deficient NK cells showed poor direct reactivity toward tumor targets as measured by cytokine production and degranulation. Unexpectedly, however, FcRγ-deficient NK cells exhibited significantly more robust responsiveness upon stimulation through CD16, particularly for cytokine production, compared to FcRγ-expressing NK cells. Thus, our study reveals FcRγ-deficient NK cells as a novel subset of human NK cells that have remarkably potent responses toward antibody-coated targets. These findings also illustrate a differential contribution of FcRγ and CD3ζ for the expression and functional activity of their associated receptors.

Relationship of NKG2C Copy Number with the Distribution of Distinct Cytomegalovirus-Induced Adaptive NK Cell Subsets

“…Analysis of NKG2C bright and FcRg 2 NK cell subset distribution in healthy blood donors Expansions of NKG2C bright and FcRg 2 NK cell subsets, associated with HCMV infection, share several phenotypic and functional features (1,6,7,29). To assess in detail their relationship, NKG2C, NKG2A, and FcRg expression were analyzed in peripheral blood NK cells from a cohort of healthy adults (n = 81; median age 32 y).…”

“…The deficiency of the FcRg adaptor appeared the most frequently detected, and alterations in the expression of other signaling molecules were greatly confined to the FcRg 2 NK cell subset (27,28). Reminiscent to observations in the NKG2C bright NK cell subset, FcRg-deficient NK cells displayed reduced NKp46 and NKp30 surface levels, maintaining CD16 expression and showing enhanced cytokine production and proliferation upon Ab-dependent activation (27,29). Though FcRg-deficient NK cells often express NKG2C and lack NKG2A, FcRg loss has also been described in NK cells lacking NKG2C expression (27,28,30).…”

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

“…In contrast, the average degranulation of NKG2C bright NK cells against HCMV-infected targets in the presence of specific Abs was comparable with the proportion of degranulating NKG2A + NK cells, despite their greater responsiveness to CD16-dependent activation and the accumulation of FcεR g-chain-deficient cells (51). Accordingly, the cytolytic potential of NK cell samples from donors containing or not NKG2C bright NK cell expansions against rituximab-coated 721.221 cells was comparable as assessed by the calcein-AM release method (data not shown).…”

Sweet Is the Memory of Past Troubles: NK Cells Remember

“…Binding of CD16 to IgG initiates the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on CD3ζ and FcεRIγ, facilitating recruitment of the tyrosine kinases, Syk and ZAP70, and resulting in NK cell-mediated cytotoxicity and cytokine production (Lanier 2003). Recently, Kim and colleagues have described a subset of CD56 + CD16 + NK cells in healthy individuals that lack expression of the signaling adaptor FcεRIγ and have reduced expression of the activating receptors NKp46 and NKp30 (Hwang et al 2012). Approximately 30 % of healthy individuals possess this NK cell subset, and it is strongly associated with CMV seropositivity (Zhang et al 2013).…”

“…Approximately 30 % of healthy individuals possess this NK cell subset, and it is strongly associated with CMV seropositivity (Zhang et al 2013). These FcεRIγ neg cells are functionally distinct, exhibiting diminished direct killing of targets, but surprisingly superior ADCC compared to FcεRIγ pos NK cells (Hwang et al 2012;Zhang et al 2013). In the presence of virus-specific antibodies, a greater frequency of FcεRIγ neg NK cells degranulates (CD107a+) and expresses IFN-γ and TNF-α than FcεRIγ pos NK cells.…”