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

Abstract

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...

Immunometabolism: From basic mechanisms to translation

“…The complement system is a pattern recognition receptor (PRR) system that has newly identified roles to regulate basic T cell metabolism and physiology 57 . In addition to secreted complement that arises from the liver, West et al review recent findings showing that T cells produce small amounts of intracellular forms of complement 58 . C3 and C5 in this setting are each cleaved to C3a and C3b and C5a and C5b by intracellular proteases.…”

Complement inhibition does not impair the clinical antiviral capabilities of virus-specific T-cell therapy

“…In such cases, a specific intracellular targeting of complement proteins C5a or C5aR1 would be required to inhibit VSTs. 7,20 These data are important for planning future studies. That certain viruses can trigger complement-mediated TMA leading to multiorgan injury and death is well described, and such cases may require concomitant therapy with complement inhibition and VSTs to control both viral illness and complement overactivation.…”

“…[4][5][6] The complement system is essential for viral immunity and complement proteins are known to direct and modify the cellular immune response to viral infections. 7,8 Thrombotic microangiopathy (TMA), a severe complication in susceptible individuals that can lead to organ failure or death, can be often triggered by viruses that can lead to complement-mediated systemic endothelial injury. [9][10][11][12][13][14] The use of complement blockers has been reported to mitigate TMA, 15 but the impact of complement blockade on the efficacy of VST activity has not yet been described.…”

Role of Complement Receptors (CRs) on DCs in Anti-HIV-1 Immunity

“…Intracellular C, especially C3, is cleaved permanently by proteases such as cathepsins and binds to intracellular C3aRs on lysosomes. This engulfment regulates cell growth, cell proliferation and cell survival via the serine/ threonine protein kinase mammalian target of rapamycin (mTOR) (56). Experiments co-culturing antigen-presenting cells (APCs) and T cells furthermore demonstrated the importance of cellular complement in terms of T helper cell development and proliferation.…”