IL-10 induces aberrant deletion of dendritic cells by natural killer cells in the context of HIV infection
Galit Alter, … , Jan van Lunzen, Marcus Altfeld
Galit Alter, … , Jan van Lunzen, Marcus Altfeld
Published May 3, 2010
Citation Information: J Clin Invest. 2010;120(6):1905-1913. https://doi.org/10.1172/JCI40913.
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Research Article Virology

IL-10 induces aberrant deletion of dendritic cells by natural killer cells in the context of HIV infection

Abstract

Persistent levels of IL-10 play a central role in progressive immune dysfunction associated with chronic viral infections such as HIV, but the underlying mechanisms are poorly understood. Because IL-10 affects the phenotypic and functional properties of DCs, which are responsible for initiating adaptive immune responses, we investigated whether IL-10 induces changes in DC phenotype and function in the context of HIV infection. Here, we show that IL-10 treatment of immature and mature human DCs in culture induced contrasting phenotypic changes in these populations: immature DCs exhibited aberrant resistance to NK cell–mediated elimination, whereas mature DCs exhibited increased susceptibility to NKG2D-dependent NK elimination. Treatment of immature and mature DCs with HIV resulted in potent IL-10 secretion and the same phenotypic and functional changes observed in the IL-10–treated cells. Consistent with these in vitro data, LNs isolated from individuals infected with HIV exhibited aberrant accumulation of a partially “immature” DC population. Together, these data suggest that the progressive immune dysfunction observed in chronic viral infections might be caused in part by IL-10–induced reversal of DC susceptibility to NK cell–mediated elimination, resulting in the accumulation of poorly immunogenic DCs in LNs, the sites of adaptive immune response induction.

Authors

Galit Alter, Daniel Kavanagh, Suzannah Rihn, Rutger Luteijn, David Brooks, Michael Oldstone, Jan van Lunzen, Marcus Altfeld

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Figure 4

NK cells eliminate IL-10–treated mature DCs in an NKG2D-dependent manner, which is blocked by IL-10R blockade.

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NK cells eliminate IL-10–treated mature DCs in an NKG2D-dependent manner...
(A) Binding capacity of an NKG2D-fusion construct and expression of MIC-A/B on immature and mature DCs in the presence of medium alone or IL-10. (B) Coexpression levels of MIC-A/B and MHC-I on the surface of immature or mature DCs in the presence and absence of IL-10. (C) Mean ± SEM capacity of NK cells to lyse IL-10–treated mature DCs in the absence or presence of an NKG2D-blocking antibody (n = 5). (D) Mean ± SEM percent lysis of mature DCs by autologous NK cells after maturation in the presence of medium alone, IL-10 alone, and IL-10 plus IL-10R–blocking antibody — either during maturation in vitro (culture) or during the NK cell/DC killing assay (killing). *P < 0.05; **P < 0.01.