Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 44, Issue 11, Pages 3368-3379Publisher
WILEY
DOI: 10.1002/eji.201444515
Keywords
ADCC; Fc receptors; Monocytes; NKcells
Categories
Funding
- Braukmann-Wittenberg-Herz-Stiftung
- Deutsche Forschungsgemeinschaft (DFG)
- Bundesministerium fur Bildung und Forschung
- Helmholtz-Zentrum fur Infektionsforschung [IG-SCID-TwinPro02]
- Stiftung Zukunfts- und Innovationsfonds Niedersachsen
- Deutsches Zentrum fur Infektionsforschung (DZIF)
- DFG [HO 4527/1-1]
- Hochschulinterne Leistungsfoerderung (HiLf) from Hannover Medical School, Germany
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Monocytes are known to engage in reciprocal crosstalk with NKcells but their influence on NK-cell-associated antibody-dependent cellular cytotoxicity (ADCC) is not well understood. We demonstrate that in humans FcRIII (CD16)-dependent ADCC by NKcells is considerably enhanced by monocytes, and that this effect is regulated by FcRII (CD32) crosslinking in healthy individuals. It is known that during HIV-1 infection, NKcells 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 NKcells 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 FcRIII-mediated NK-cell functions maintaining a well-balanced immune response.
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