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

Abstract

Natural killer (NK) cells belong to the innate immune system and protect against cancers and a variety of viruses including retroviruses by killing transformed or infected cells. They express activating and inhibitory receptors on their cell surface and often become activated after recognizing virus-infected cells. They have diverse antiviral effector functions like the release of cytotoxic granules, cytokine production and antibody dependent cellular cytotoxicity. The importance of NK cell activity in retroviral infections became evident due to the discovery of several viral strategies to escape recognition and elimination by NK cells. Mutational sequence polymorphisms as well as modulation of surface receptors and their ligands are mechanisms of the human immunodeficiency virus-1 to evade NK cell-mediated immune pressure. In Friend retrovirus infected mice the virus can manipulate molecular or cellular immune factors that in turn suppress the NK cell response. In this model NK cells lack cytokines for optimal activation and can be functionally suppressed by regulatory T cells. However, these inhibitory pathways can be overcome therapeutically to achieve full activation of NK cell responses and ultimately control dissemination of retroviral infection. One effective approach is to modulate the crosstalk between NK cells and dendritic cells, which produce NK cell-stimulating cytokines like type I interferons (IFN), IL-12, IL-15, and IL-18 upon retrovirus sensing or infection. Therapeutic administration of IFNα directly increases NK cell killing of retrovirus-infected cells. In addition, IL-2/anti-IL-2 complexes that direct IL-2 to NK cells have been shown to significantly improve control of retroviral infection by NK cells in vivo. In this review, we describe novel approaches to improve NK cell effector functions in retroviral infections. Immunotherapies that target NK cells of patients suffering from viral infections might be a promising treatment option for the future.

Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial

“…In contrast to increased infection risk associated with standard therapies in SLE, we observed no serious infection in previous study,11 which was in line with the report showing that low-dose IL-2 ameliorated hepatitis C virus-induced vasculitis without increasing viral load 13. From an immunological perspective, IL-2 treatment may enhance virus-specific CD8 + T cell responses18 and promote the activity of NK cells against infections 19 20…”

“…In this study, the CD56 bright NK subset was preferentially expanded by low-dose IL-2, and might contribute to the alleviation of SLE autoimmunity together with expanded Treg cells. NK cells are also important in protection against viral infections 19 20. We observed significantly increased expression of IFNγ, NKp46 and NKG2D by NK cells in response to low-dose IL-2 treatment (online supplementary table S11), which implicated potential augmentation of anti-infectious cellular immunity.…”

“…The concept of low-dose IL-2 therapy in autoimmunity and inflammation was inspired by the key role of IL-2 in the development and function of Treg cells, which are essential in maintaining immune tolerance. Instead of promoting immunity by high-dose IL-2, open-labelled trials suggested that low-dose IL-2 suppressed inflammation and autoimmunity in hepatitis C-associated vasculitis, graft-versus-host disease, type 1 diabetes, alopecia areata and SLE 11–13 17–20. Low-dose IL-2 treatment was reported safe and associated with clinical improvements in these studies.…”

Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity

“…Here TLR-9 (Olbrich et al 2002) and TLR-3 ligands (Gibbert et al 2010) mediated IFN-dependent direct anti-viral activity as well as stimulatory effects on virus-specific T cells. Beside IFNα subtypes, other cytokines that enhance NK cell responses were shown to restrict initial FV replication, including IL-2 specifically targeted to NK cells (Littwitz-Salomon et al 2015) and IL-15/IL-18 (Littwitz-Salomon, Dittmer and Sutter 2016;Littwitz-Salomon, Schimmer and Dittmer 2017a). In contrast to IFNα, these effects exclusively relied on the activity of NK cells and no other immunological mechanisms were involved.…”

Heterogeneity of Nk and NKT Lymphocyte Populations in Healthy Donors

“…Оказалось, что различие между определени-ем с помощью тест-системы CD3/CD16/CD56 и с помощью CD3/CD16 является статистически значимым (p < 0,05). Было показано, что основ- , на долю кото-рых приходится до 10% [13,20,25,27].…”