Activated regulatory T cells suppress effector NK cell responses by an IL-2-mediated mechanism during an acute retroviral infection

Abstract

BackgroundIt is well established that effector T cell responses are crucial for the control of most virus infections, but they are often tightly controlled by regulatory T cells (Treg) to minimize immunopathology. NK cells also contribute to virus control but it is not known if their antiviral effect is influenced by virus-induced Tregs as well. We therefore analyzed whether antiretroviral NK cell functions are inhibited by Tregs during an acute Friend retrovirus infection of mice.ResultsSelective depletion of Tregs by using the transgenic DEREG mouse model resulted in improved NK cell proliferation, maturation and effector cell differentiation. Suppression of NK cell functions depended on IL-2 consumption by Tregs, which could be overcome by specific NK cell stimulation with an IL-2/anti-IL-2 mAb complex.ConclusionsThe current study demonstrates that virus-induced Tregs indeed inhibit antiviral NK cell responses and describes a targeted immunotherapy that can abrogate the suppression of NK cells by Tregs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0191-3) contains supplementary material, which is available to authorized users.

Insufficient natural killer cell responses against retroviruses: how to improve NK cell killing of retrovirus-infected cells

“…The IL-2 mAb S4B6 complex has already been shown to improve NK cell responses and subsequent clearance of tumor cells [100, 149]. In the FV model, an up to 90% reduction in viral loads was demonstrated after specific stimulation of NK cells with IL-2 mAb S4B6 complex [100]. In this study, proliferation and maturation of NK cells as well as activation and effector functions were significantly improved.…”

“…It was therefore likely that retrovirus-induced Tregs also inhibit antiviral NK cell responses. Indeed, we recently demonstrated that specific ablation of Tregs in FV infected mice improved the activation, cytokine production, and cytotoxic activity of NK cells [100]. Competition for IL-2 was found to be the main molecular mechanism of Treg–NK cell suppression (Fig.…”

“…Treatment with specific IL-2/anti-IL-2 mAb complexes also circumvents severe side effects of high dose IL-2 therapy and results in increased half-life of IL-2 in vivo [147, 148]. The IL-2 mAb S4B6 complex has already been shown to improve NK cell responses and subsequent clearance of tumor cells [100, 149]. In the FV model, an up to 90% reduction in viral loads was demonstrated after specific stimulation of NK cells with IL-2 mAb S4B6 complex [100].…”

The aryl hydrocarbon receptor modulates the function of human CD56bright NK cells

“…Modulation of IL2Rα (CD25) could result in differences in the ability of CD56 bright NK cells to respond to IL‐2 stimulation. Alternatively, modulation of CD25 may result in a gain of immunomodulatory potential by making CD56 bright NK cells able to regulate the availability of IL‐2 in the microenvironment, a feature previously described for Tregs .…”

Depletion of FoxP3+ Tregs improves control of larval Echinococcus multilocularis infection by promoting co‐stimulation and Th1/17 immunity

“…Influence of regulatory T cell depletion on the outcome of infection has been shown in several models. Littwitz‐Salomon et al showed a strong increase of NK cell maturation, activation and effector functions in Treg‐depleted mice, and activated regulatory T cells suppressed effector NK cell responses by an IL‐2‐mediated mechanism during an acute retroviral infection. Another study showed a significantly increased IL‐6 level and a trend toward higher levels of TNF‐α in Treg‐depleted mice during sepsis, which supported the hypothesis that the hyper‐inflammatory response during the early phase of sepsis was intensified in mice lacking Treg cells.…”