FcγRIII (CD16)‐mediated ADCC by NK cells is regulated by monocytes and FcγRII (CD32)

Abstract

Monocytes are known to engage in reciprocal crosstalk with NK cells but their influence on NK-cell-associated antibody-dependent cellular cytotoxicity (ADCC) is not well understood. We demonstrate that in humans FcγRIII (CD16)-dependent ADCC by NK cells is considerably enhanced by monocytes, and that this effect is regulated by FcγRII (CD32) crosslinking in healthy individuals. It is known that during HIV-1 infection, NK cells are known to express low levels of CD16 and exhibit reduced ADCC.We show that immune regulation of CD16-mediated NK-cell cytotoxicity by monocytes through CD32 engagement is substantially disturbed in chronic progressive HIV-1 infection. Expression of activating isoform of CD32 represented a compensatory mechanism for reduced expression of CD16 on NK cells during HIV-1 infection. As a result, the regulation of NK-cell-associated ADCC by monocytes is skewed and eventually constitutes a novel factor that contributes to HIV-1-associated immune deficiency, dysregulation and pathogenesis. Our data therefore provide evidence, for the first time, that in humans monocytes act as a rheostat for FcγRIII-mediated NK-cell functions maintaining a well-balanced immune response. Keywords: ADCC r Fcγ receptors r Monocytes r NK cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site Introduction NK cells are an important arm of innate immunity; they can kill tumor cells and virus-infected cells without prior sensitization, produce cytokines, and are involved in immune regulation. NK cells destroy their targets by natural cellular cytotoxicity (NCC)Correspondence: Dr. Dirk Meyer-Olson e-mail: dirk.meyer-olson@fachklinik-bad-pyrmont.de or antibody-dependent cellular cytotoxicity (ADCC) [1,2]. In antibody-mediated immune responses such as ADCC, Fc receptors bind to the Fc portion of antibody-coated target cells, which result in triggering of activating or inhibitory signaling pathways, thereby regulating the release of cytolytic granules and inflammatory mediators such as cytokines and chemokines [1,3]. Three different classes of Fcγ receptors have been described in humans, the high affinity FcγRI (CD64), and the medium-low affinity FcγRII (CD32), and FcγRIII (CD16) [4]. Various cell types such as NK cells, monocytes, neutrophils, and eosinophils are known C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 3368-3379 Innate immunity 3369 to perform ADCC. NK cells perform ADCC primarily via CD16, triggering target cell lysis and cytokine production [1,3]. Three different isoforms of CD32 are expressed on human cells: the activating receptors CD32A and CD32C, as well as the inhibitory receptor CD32B [3,5]. NK cells are thought to express mostly the activating isoform of the receptor, CD32C [6]. The role of Fc receptors in various diseases has been well documented: genetic polymorphisms in CD16 and CD32 have provided evidence for their implication in several infectious and autoimmune diseases highlighting...

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