A novel subset of NK cells expressing high levels of inhibitory FcγRIIB modulating antibody-dependent function

Abstract

NK cells can kill antibody-coated target cells following engagement of FcgammaRIIIA, the major activating FcgammaR expressed by these cells. The presence of FcgammaRIIC (CD32C) has also been reported, but its contribution to the FcgammaR-dependent effector functions of NK cells remains debated. We demonstrate here that inhibitory FcgammaRIIB is also expressed by a small subset of CD56+/NKp46+ NK cells and can efficiently down-modulate their FcgammaR-dependent effector function. Immunofluorescence analyses of NK cells from 52 healthy donors showed the presence of CD56bright/FcgammaRII(-) (5.2%+/-3.4), CD56dim/FcgammaRII(lo/-) (94.1%+/-3.4), and CD56dim/FcgammaRIIbright (0.64%+/-0.72) cells. QRT-PCR and protein analyses performed on isolated FcgammaRIIbright NK cells indicated that FcgammaRIIB is strongly expressed by these cells but not by FcgammaRII(lo/-) cells. In addition, FcgammaRIIbright cells showed a weaker antibody-dependent degranulation when incubated with IgG-coated target cells compared with FcgammaRII(lo/-) NK cells, although a strong FcgammaRIIIA expression was detected in both cells. Furthermore, the addition of anti-FcgammaRII Fab paralleled a higher degranulation of FcgammaRIIbright NK cells, indicating a direct role for FcgammaRIIB in this down-modulating effect. Thus, it is proposed that FcgammaRIIBbright NK cells represent a new NK cell compartment able to down-modulate NK cell functions triggered by the engagement of activating FcgammaR.

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation

“…The inhibitory receptor CD32B, classically considered to be expressed only on B lymphocytes or myeloid cells, and the activating receptor CD32C, which is generally not expressed, can both be detected on the NK cells of some individuals. Their expression on this lymphocyte subset was reported to modulate ADCC potency in some, but not all, assays (15,16,59,60). In our in vitro setting of HSV-1 infection, significant CD32B and CD32C contributions to NK cell-mediated ADCC were undetectable.…”

FcγRs in Health and Disease

“…An exception to this rule is NK cells which solely express FcgRIIIA (CD16) in humans and FcgRIII in mice. Recently, a small subpopulation of NK cells has been shown to express FcgRIIB, although the functional role of this NK cell subset remains to be established (Dutertre et al 2008). B cells do not express activating FcgRs, but express the inhibitory Fc-receptor, which regulates positive signals initiated via the B cell receptor.…”

Three major uncertainties in the antibody therapy of cancer

“…Cells fitting such a description are monocytes/macrophages, dendritic cells, and neutrophils. 39 NK cells, the cells used routinely to assess ADCC function in candidate anti-tumor antibodies, have not been shown to express the inhibitory FcγRIIB (apart from a subpopulation of mouse NK cells comprising <1% of the total 40 ). These facts led to the conclusion that macrophages are the major effector cells involved.…”