IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

Abstract

16Dynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly 17 influence immune cell function and differentiation including Natural Killer (NK) cell responses. 18Persistent HIV-1 infection leads to a state of chronic activation, subset redistribution and progressive 45 et al., 2015) (Lee et al., 2015). The adaptive reconfiguration of NK cells during HIV-1 infection is further 46 delineated by loss of the transcription factor promyelocytic leukaemia zinc finger protein (PLZF), and 47 downstream signalling molecules such as FcεRI-γ (Peppa et al., 2018), which partly overlap with 48 NKG2C expression. While these attributes are considered important in the functional specialisation of 49 2 these NK cells, the development of these features under conditions of continuous 50 stimulation/persistent inflammation during HIV-1 infection could lead to the establishment of 51 functionally and metabolically exhausted NK cells akin to exhausted CD8 T cells. In keeping with this 52 notion, chronic stimulation of adaptive NK cells through NKG2C ligation was recently found to lead to 53 a molecular programme of exhaustion that is shared between NK cells and CD8 T cells (Merino et al., 54 2019). Exhausted CD8 T cells are characterised by a number of metabolic defects, however, to date it 55 remains unexplored how persistent HIV-1 infection contributes to the metabolic remodelling of NK 56 cell subsets. NK cell exhaustion could influence responses to CD16 engagement linked to vaccine-57 induced protective immunity against HIV-1 infection and phenotypes of viral control (Scully and Alter, 58 2016). Such knowledge represents a critical first step in our understanding of the metabolic machinery 59 of NK cell subsets with distinct immunologic features that can be potentially targeted for developing 60 new or complementary antiviral approaches aimed at enhancing ADCC responses. 61 62 Whereas metabolic regulation of T cell function is well characterised, evidence of the importance of 63 immunometabolism in facilitating robust NK cell functions is gradually emerging. Notably, impaired 64 NK cell cellular metabolism has been implicated in obesity and cancer, providing a new framework for 65 understanding NK cell functionality (Michelet et al., 2018) (Cong et al., 2018). Studies from both 66 human and murine models have demonstrated that NK cells activated through cytokine stimulation 67 exhibit substantial increases in the rates of both glycolysis and oxidative phosphorylation (OXPHOS) 68 pathways (Marcais et al., 2014) (Donnelly et al., 2014) (Keating et al., 2016; O'Brien and Finlay, 2019). 69However, the metabolic requirement of NK cells for optimal effector function, in terms of IFN- 70 production, depends on the specific activation stimuli. In particular, receptor mediated activation 71 through anti-NK1.1 and anti-Ly49D in mice appears to require OXPHOS as an essential second signal 72 for IFN- production and appears more susceptible to metabolic inhibition compared to cytokine 73 stimulation ...

Metabolic requirements of NK cells during the acute response against retroviral infection

“…Thus, the FV infection is a good experimental model when analysing NK cells and metabolic requirements for their responses against retroviruses. In chronically HIV-infected individuals, co-infected with cytomegalovirus (CMV), NK cells show evidence of mitochondria dysfunction and reduced levels of OXPHOS 21 . Targeting immune cell metabolism is an extremely promising therapeutic approach that has been investigated for numerous immunological diseases [22][23][24] .…”

Alterations in mitochondrial morphology as a key driver of immunity and host defence

“…With regard to infection, NK cells have an important role in immune control of human immunodeficiency virus (HIV‐1) infection, and again mitochondrial dynamics may impact this response. NK cells isolated from HIV‐1/human cytomegalovirus (HCMV) seropositive donors exhibited small spherical mitochondrial shape, whereas those from HIV‐1/HCMV seronegative donors showed long and tubular mitochondrial morphology (Fig 2 ) (preprint: Cubero et al , 2019 ). The direct implications of mitochondrial dynamics of NK cell function in HIV infection are still unclear.…”

Metabolism of Natural Killer Cells and Other Innate Lymphoid Cells

“…IL-15 pre-treatment could bypass the metabolic requirement of NK cells for receptor ligation and potentiate NK cell functions. Indeed, activation of NK cells by stimulation of activating receptors has been demonstrated to be an energy-demanding process ( 39 , 110 ).…”

“…On the other hand, IL-15 priming has been demonstrated to reduce NK cell reliance on cellular metabolism, hence, IL-15 agonists may be effective for enhancing NK cell function in metabolically challenging environments, including viral infections and cancers ( 67 , 110 ).…”

“…This scenario results in deterioration of NK cell effector functions and is often accompanied by upregulation of inhibitory receptors, such as PD-1, NKG2A, and Tim-3, a status akin to CD8 + T cell exhaustion (106)(107)(108)(109). Further, a recent study by Cubero et al showed that, during chronic HIV-1 infection, NK cells exhibited metabolic defects bearing similarities to exhausted CD8 + T cells (110). Persistent HIV-1 infection led to NK cell mitochondrial dysfunction, characterized by defective OXPHOS, increased mitochondrial depolarization and fragmented mitochondria, which limited the ability of NK cells to mobilize alternative fuels to power IFN-γ production upon activating receptor stimulation; a state of metabolic inflexibility.…”