Metabolic Profiling Using Stable Isotope Tracing Reveals Distinct Patterns of Glucose Utilization by Physiologically Activated CD8+ T Cells

265

190

Immunometabolism has emerged as a major mechanism central to adaptive and innate immune regulation. From early observations that inflammatory cytokines were induced in obese adipose tissue and that these cytokines contributed to metabolic disease, it was clear that metabolism and the immunological state are inextricably linked. With a second research wave arising from studies in cancer metabolism to also study the intrinsic metabolic pathways of immune cells themselves and how those pathways influence cell fate and function, immunometabolism is a rapidly maturing area of research. Several key themes and goals drive the field. There is abundant evidence that metabolic pathways are closely tied to cell signaling and differentiation which leads different subsets of immune cells to adopt unique metabolic programs specific to their state and environment. In this way, metabolic signaling drives cell fate. It is also apparent that microenvironment greatly influences cell metabolism.Immune cells adopt programs specific for the tissues where they infiltrate and reside.Ultimately, a central goal of the field is to apply immunometabolism findings to the discovery of novel therapeutic strategies in a wide range of diseases, including cancer, autoimmunity, and metabolic syndrome. This review summarizes these facets of immunometabolism and highlights opportunities for clinical translation. K E Y W O R D S autoimmunity, immune-mediated diseases, infectious diseases, metThis article introduces a series of reviews covering Immunometabolism: From Basic Mechanisms to Translation appearing in Volume 295 of Immunological Reviews.

Section: Immunome Tabolis M In Tissue Smentioning

confidence: 99%

Immunometabolism: From basic mechanisms to translation

Makowski

Chaib

Rathmell

2020

265

190

“…However, even if specific gene mutations have been clearly defined via exome sequencing, one cannot exclude that undetected confounding factors contribute to observed disease pathology in these patients. More importantly, ex vivo analysis of cells may not reflect their in vivo behavior-which is particularly problematic for the analysis of cell metabolism 141 Another current barrier in rapidly moving complement-metabolism research forward is the finding that complosome components present in both mice and men do not always have overlapping locations of expression and may not always serve similar functions. For example, while expression of C3aR and C5aR1 and 2 by human CD4 + T cells is broadly acknowledged, 15,72 their presence in mouse T cells is a matter of ongoing debate with some groups observing C3aR, or C5aR1 or 2 expression on resting or activated T cells 18,144 and others failing to replicate these findings.…”

Section: Current H Urdle S In D Iss Ec Ting the Complosome-me Tabolmentioning

confidence: 99%

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

West

Kunz

Kemper

2020

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...

“…190 These studies have been however largely performed with in vitro polarization conditions, and a sophisticated isotope tracing analysis has challenged the high glycolysis requirement of activated T cells in physiological conditions in live mice. 191 Tfh cells in lupus mice present a high level of mTORC1 activation, and they are the most glycolytic CD4 + T cells in these mice. Accordingly, the frequency of Tfh cells, as well as that of GC B cells and the resulting production of autoantibodies, was reduced to non-autoimmune levels by a treatment with 2DG in several mouse models of lupus.…”

Section: Numbers Of Activated Cd4 + T Cells and Gc B Cells Inhibitedmentioning

confidence: 99%

Metabolic determinants of lupus pathogenesis

Teng

Brown

Choi

et al. 2020

The metabolism of healthy murine and more recently human immune cells has been investigated with an increasing amount of details. These studies have revealed the challenges presented by immune cells to respond rapidly to a wide variety of triggers by adjusting the amount, type, and utilization of the nutrients they import. A concept has emerged that cellular metabolic programs regulate the size of the immune response and the plasticity of its effector functions. This has generated a lot of enthusiasm with the prediction that cellular metabolism could be manipulated to either enhance or limit an immune response. In support of this hypothesis, studies in animal models as well as human subjects have shown that the dysregulation of the immune system in autoimmune diseases is associated with a skewing of the immunometabolic programs. These studies have been mostly conducted on autoimmune CD4 + T cells, with the metabolism of other immune cells in autoimmune settings still being understudied. Here we discuss systemic metabolism as well as cellular immunometabolism as novel tools to decipher fundamental mechanisms of autoimmunity. We review the contribution of each major metabolic pathway to autoimmune diseases, with a focus on systemic lupus erythematosus (SLE), with the relevant translational opportunities, existing or predicted from results obtained with healthy immune cells. Finally, we review how targeting metabolic programs may present novel therapeutic venues. K E Y W O R D Sglucose, glutamine, lupus, metabolic inhibitors, metabolism