Lymphocyte Activation Gene-3 Maintains Mitochondrial and Metabolic Quiescence in Naive CD4+ T Cells

Previte, Dana M.; Martins, Christina; O’Connor, Erin C.; Marre, M; Coudriet, Gina M.; Beck, Noah W.; Menk, Ashley V.; Wright, Rebecca H.; Tse, Hubert M.; Delgoffe, Greg M.; Piganelli, Jon D.

doi:10.1016/j.celrep.2019.03.004

Cited by 61 publications

(56 citation statements)

References 49 publications

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“…Some work has begun to show that these molecules may also signal in a tonic tonic fashion, which may regulate T cell function. For instance, Previte and colleagues investigated the role of the inhibitory lymphocyte activation gene‐3 (LAG‐3) in controling naïve T cell metabolism . In their work, the authors found that genetic deletion of LAG‐3 induced T cells to be more metabolically active and more proliferative under homeostatic conditions in an adoptive transfer model.…”

Section: Outlook: Tonic Signals and Cancer Immunotherapy?mentioning

confidence: 99%

mTOR and other effector kinase signals that impact T cell function and activity

Myers

Wheeler

Roose

2019

Immunological Reviews

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T cells play important roles in autoimmune diseases and cancer. Following the cloning of the T cell receptor (TCR), the race was on to map signaling proteins that contributed to T cell activation downstream of the TCR as well as co-stimulatory molecules such as CD28. We term this "canonical TCR signaling" here. More recently, it has been appreciated that T cells need to accommodate increased metabolic needs that stem from T cell activation in order to function properly. A central role herein has emerged for mechanistic/mammalian target of rapamycin (mTOR). In this review we briefly cover canonical TCR signaling to set the stage for discussion on mTOR signaling, mRNA translation, and metabolic adaptation in T cells. We also discuss the role of mTOR in follicular helper T cells, regulatory T cells, and other T cell subsets. Our lab recently uncovered that "tonic signals", which pass through proximal TCR signaling components, are robustly and selectively transduced to mTOR to promote baseline translation of various mRNA targets. We discuss insights on (tonic) mTOR signaling in the context of T cell function in autoimmune diseases such as lupus as well as in cancer immunotherapy through CAR-T cell or checkpoint blockade approaches. K E Y W O R D Sautoimmune, cancer, mammalian target of rapamycin, signaling, T cell, tonic | 135 MYERS Et al

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Section: Outlook: Tonic Signals and Cancer Immunotherapy?mentioning

confidence: 99%

mTOR and other effector kinase signals that impact T cell function and activity

Myers

Wheeler

Roose

2019

Immunological Reviews

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“…Recently chronic stimulation of adaptive NKG2C+ NK cells in vitro led to a marked induction of checkpoint inhibitory receptors PD-1 and lymphocyte activation gene-3 (LAG-3) sharing epigenetically driven programmes with exhausted CD8 T cells (Merino et al, 2019). Moreover, a role for LAG-3 in regulating CD4 T cell metabolism and mitochondrial biogenesis has been identified (Previte et al, 2019). We have previously reported a modest increase in the levels of PD-1 expression on NK cells in HIV-1 infection (Peppa et al, 2018), however, the role of inhibitory receptors in controlling NK cell metabolism remains to be further defined.…”

Section: Discussionmentioning

confidence: 99%

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

Cubero

Balint

Alrubayyi³

et al. 2019

Preprint

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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 ...

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“…LAG-3 was shown to modulate bioenergetics of T cells. Specifically, expression of LAG-3 on CD4 + T cells inhibited mitochondrial biogenesis and metabolism [91]. LAG-3-deficient T cells were also more glycolytically active than wild-type T cells.…”

Section: Lag-3mentioning

confidence: 95%

Immunometabolic Responses of Natural Killer Cells to Inhibitory Tumor Microenvironment Checkpoints

Dao

Matosevic

2019

Immunometabolism

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NK cell trafficking and migration into solid tumors is often poor. Altered NK cell metabolism in the tumor microenvironment has been correlated with tumor invasiveness, metastasis and cellular dysfunction. Tumorinduced stresses correlate to limited numbers of functional NK cells in solid tumors and, consequently, limited survival. Metabolic impairment of NK cells in cancer is still not fully understood, but the involvement of inhibitory checkpoints-both tumor-associated as well as NK-specificplays a significant role in driving these responses. The metabolic reprogramming events that NK cells undergo in the tumor microenvironment are linked to their ability to support energy metabolism in scenarios of impaired glycolytic fueling and low oxygen. The contributions of inhibitory checkpoints to these events are not entirely known, but are emerging as increasingly significant to the restoration of NK cell function. Here, we discuss our understanding of the role of inhibitory receptors and checkpoints in the metabolic dysfunction of NK cells in solid tumors, as a critical key to the development of new immunotherapies.

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Lymphocyte Activation Gene-3 Maintains Mitochondrial and Metabolic Quiescence in Naive CD4+ T Cells

Cited by 61 publications

References 49 publications

mTOR and other effector kinase signals that impact T cell function and activity

mTOR and other effector kinase signals that impact T cell function and activity

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

Immunometabolic Responses of Natural Killer Cells to Inhibitory Tumor Microenvironment Checkpoints

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