Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism

Johnson, Marc O.; Wolf, Melissa M.; Madden, Matthew Z.; Andrejeva, Gabriela; Sugiura, Ayaka; Contreras, Diana C.; Maseda, Damián; Liberti, Maria V.; Paz, Katelyn; Kishton, Rigel J.; Johnson, Matthew E.; Cubas, Aguirre A. de; Wu, Pingsheng; Li, Gongbo; Zhang, Yongliang; Newcomb, Dawn C.; Wells, Andrew D.; Restifo, Nicholas P.; Rathmell, W. Kimryn; Locasale, Jason W.; Davila, Marco L.; Blazar, Bruce R.; Rathmell, Jeffrey C.

doi:10.1016/j.cell.2018.10.001

Cited by 518 publications

(454 citation statements)

References 56 publications

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“…Of note, while we know that CTSL can activate C3 within cells, the protease(s) or enzyme complex(es) that process C5 into active C5a and C5b are currently not defined. 72 39,43,45,73,74 Interestingly, CD46 and serum C3-deficient patients have unaltered Th2 responses and we have not been able to observe a defect in their T cell proliferation, at least upon ex vivo assessment. 48,49,68 The reason for this intimate relationship between the complosome and IFN-γ is currently not clear but may also be rooted in their close co-evolution (see below).…”

Section: The Complosome In T Cell Homeostasismentioning

confidence: 66%

Complement and human T cell metabolism: Location, location, location

West

Kunz

Kemper

2020

Immunological Reviews

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Immunological Reviews. 2020;295:68-81. wileyonlinelibrary.com/journal/imr 1 | INTRODUC TI ON Our contemporary immune system has evolved under the constant pressure from a broad range of pathogens that manipulate the host to enhance their own propagation. As diverse as the pathogenic threats are, ranging from intra-and extracellular bacteria, viruses, fungi, and complex parasites, as elegant and effective are the defense mechanisms developed and employed by the host to combat this constant onslaught. Particularly, the detection systems that are functioning as the first lines of defense against such invaders are formidable. If a microbe has managed to penetrate the protective physical barriers, such as the skin, or lung, a range of innate immune sensors either circulating in the blood, lymph, and interstitial fluids or expressed in and on scavenger and sentinel cells, such as neutrophils and microphages, detect the conserved pathogen-associated molecular patterns (PAMPs). These sensor systems comprise several pattern recognition receptors (PRRs) and include the Toll-like receptors (TLRs), the NOD-like receptors (NLRs), the retinoic acid-inducible gene-I (RIG)-like system, several distinct inflammasomes, and the complement system-derived receptors. 1,2 Activation of PRRs by a pathogen is most often triggered in several sensor systems in parallel and then initiates the general inflammatory reaction as well as tailored immune cell activation specifically effective toward the identified pathogen. The ability of PRR systems to decisively discriminate between a real threat, that is non-self and dangerous self via recognizing so-called danger-associated molecular patterns (DAMPs), and self and harmless alterations of self is critical for our health. Thus, there are several checks and balances build into the PRR systems that prevent unwanted reactions against sensed AbstractThe complement system represents one of the evolutionary oldest arms of our immune system and is commonly recognized as a liver-derived and serum-active system critical for providing protection against invading pathogens. Recent unexpected findings, however, have defined novel and rather "uncommon" locations and activities of complement. Specifically, the discovery of an intracellularly active complement system-the complosome-and its key role in the regulation of cell metabolic pathways that underly normal human T cell responses have taught us that there is still much to be discovered about this system. Here, we summarize the current knowledge about the emerging functions of the complosome in T cell metabolism. We further place complosome activities among the non-canonical roles of other intracellular innate danger sensing systems and argue that a "location-centric" view of complement evolution could logically justify its close connection with the regulation of basic cell physiology. K E Y W O R D S CD46, complement, complosome, metabolism, T cells | 69 WEST ET al.innocuous antigens. However, PRRs not only take care to contain tissue injury during their...

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Section: The Complosome In T Cell Homeostasismentioning

confidence: 66%

Complement and human T cell metabolism: Location, location, location

West

Kunz

Kemper

2020

Immunological Reviews

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“…Our data also showed an important decrease in TNF-α and IFN-γ-producing CD4 and CD8 T cells. Previous reports have shown that GLS null T cells failed to drive Th17-inflammatory diseases contributing to Th1 exhaustion cells over time [34]. Additionally, glutamine deprivation or deletion of SLC1A5 was shown to promote Foxp3 expression, the transcription factor of regulatory T cells [15,39].…”

Section: Discussionmentioning

confidence: 96%

“…In contrary, depletion of glutamine reduced the cytotoxic activity. In our co-culture system, it is plausible that a decreased bioavailability of glutamine is significantly hampering the cytotoxicity given that glutamine depletion blocks T cell proliferation and cytokine production [33,34]. Interestingly, in vivo administration of BPTES, a GLS inhibitor, led to a reduction on the surface expression of MHC class II and CD80 molecules, essential for antigen presentation and T cell co-stimulation [35,36], on myeloid cells recruited to the spleen than that observed in non-treated L. donovani-infected mice.…”

Section: Discussionmentioning

confidence: 99%

Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis

et al. 2020

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BackgroundThe disturbance of host metabolic pathways by Leishmania parasites has crucial consequences for the activation status of immune cells and the outcome of infection. Glutamine has been described as an immunomodulatory amino acid, yet its role during Leishmania infection is still unknown.Visceral leishmaniasis is a life threatening neglected tropical disease affecting around 500,000 and killing 50,000 individuals a year. Despite its obligatory dependence on host cell metabolism and the lack of effective, non-toxic, orally bioavailable anti-leishmanial drugs, Leishmania-perturbed host cell metabolomes and its relation to anti-leishmanial chemotherapy remains unexplored. Transcriptomic analysis performed on L. donovaniinfected macrophages identified patterns of gene expression associated with glutamine metabolism. In vitro and in vivo pharmacological inhibition of glutaminase (GLS), which catalyzes the first reaction in the primary pathway for the catabolism of glutamine, significantly increased the susceptibility to infection demonstrating the role of glutamine metabolism to L. donovani infection. More importantly, we demonstrated that glutamine supplementation during miltefosine treatment potentiates L. donovani clearance through the development of a more effective anti-Leishmania innate and adaptive immune response. Overall, our work demonstrated that glutamine-miltefosine synergy is a novel combined host-and pathogen-directed treatment for combating visceral leishmaniasis.

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“…Indeed, emerging evidence reveals that specific metabolites and metabolic enzymes can modulate immune cell fate decisions. For instance, glutaminase-dependent metabolism reciprocally regulates Th1 and Th17 cell differentiation (Johnson et al, 2018). Our study suggests that development of iNKT1, but not iNKT17 cells, is dependent upon mitochondrial fusion, which may be further linked to the roles of intracellular ROS in iNKT cell subset differentiation (Pyaram et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Hippo/Mst signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions

Raynor

Liu

Dhungana

et al. 2020

Journal of Experimental Medicine

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Invariant natural killer T (iNKT) cells acquire effector functions during development by mechanisms that remain poorly understood. Here, we show that the Hippo kinases Mst1 and Mst2 act as molecular rheostats for the terminal maturation and effector differentiation programs of iNKT cells. Loss of Mst1 alone or together with Mst2 impedes iNKT cell development, associated with defective IL-15–dependent cell survival. Mechanistically, Mst1 enforces iNKT cellular and transcriptional quiescence associated with maturation and commitment to iNKT1 cells by suppressing proliferation and Opa1-related mitochondrial metabolism that are dynamically regulated during iNKT cell development. Furthermore, Mst1 shapes the reciprocal fate decisions between iNKT1 and iNKT17 effector cells, which respectively depend upon mitochondrial dynamics and ICOS–mTORC2 signaling. Collectively, these findings establish Mst1 as a crucial regulator of mitochondrial homeostasis and quiescence in iNKT cell development and effector lineage differentiation and highlight that establishment of quiescence programs underlies iNKT cell development and effector maturation.

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Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism

Cited by 518 publications

References 56 publications

Complement and human T cell metabolism: Location, location, location

Complement and human T cell metabolism: Location, location, location

Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis

Hippo/Mst signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions

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