Highlights d Diapedesis induces C3 expression as a feature of immune cells in tissue d C3 transcription is LFA-1 dependent and integral to normal immune cell activity d Defective C3 expression underlies human primary immune deficiency disease LAD-1 d The integrin network is a key driver of complosome activity and cell function

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...

Mitochondrial C5aR1 signaling is required for proinflammatory macrophage activity during crystal-induced sterile inflammation.

Although advances in medical care have significantly improved sepsis survival, sepsis remains the leading cause of death in the ICU. This is likely due to a lack of complete understanding of the pathophysiologic mechanisms that lead to dysfunctional immunity. Neutrophil derived microparticles (NDMPs) have been shown to be the predominant microparticle present at infectious and inflamed foci in human models, however their effect on the immune response to inflammation and infection is sepsis has not been fully elucidated. As NDMPs may be a potential diagnostic and therapeutic target, we sought to determine the impact NDMPs on the immune response to a murine polymicrobial sepsis. We found that peritoneal neutrophil numbers, bacterial loads, and NDMPs were increased in our abdominal sepsis model. When NDMPs were injected into septic mice, we observed increased bacterial load, decreased neutrophil recruitment, increased expression of IL-10 and worsened mortality. Furthermore, the NDMPs express phosphatidylserine and are ingested by F4/80 macrophages via a Tim-4 and MFG-E8 dependent mechanism. Finally, upon treatment, NDMPs decrease macrophage activation, increase IL-10 release and decrease macrophage numbers. Altogether, these data suggest that NDMPs enhance immune dysfunction in sepsis by blunting the function of neutrophils and macrophages, two key cell populations involved in the early immune response to infection.

The differentiation of CD4 T cells into Th1 and Th2 cells in vivo is difficult to analyze since it is influenced by many factors such as genetic background of the mice, nature of antigen, and adjuvant. In this study, we used a well-established model, which allows inducing Th1 or Th2 cells simply by low (LD, 105) or high dose (HD, 109) injection of sheep red blood cells (SRBC) into C57BL/6 mice. Signature cytokine mRNA expression was determined in specific splenic compartments after isolation by laser-microdissection. LD immunization with SRBC induced T cell proliferation in the splenic T cell zone but no Th1 differentiation. A second administration of SRBC into the skin rapidly generated Th1 cells. In contrast, HD immunization with SRBC induced both T cell proliferation and immediate Th2 differentiation. In addition, splenic marginal zone and B cell zone were activated indicating B cells as antigen presenting cells. Interestingly, disruption of the splenic architecture, in particular of the marginal zone, abolished Th2 differentiation and led to the generation of Th1 cells, confirming that antigen presentation by B cells directs Th2 polarization. Only in its absence Th1 cells develop. Therefore, B cells might be promising targets in order to therapeutically modulate the T cell response.

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The classical liver-derived and serum-effective complement system is well appreciated as a key mediator of host protection via instruction of innate and adaptive immunity. However, recent studies have discovered an intracellularly active complement system, the complosome, which has emerged as a central regulator of the core metabolic pathways fueling human immune cell activity. Induction of expression of components of the complosome, particularly complement component C3, during transmigration from the circulation into peripheral tissues is a defining characteristic of monocytes and T cells in tissues. Intracellular complement activity is required to induce metabolic reprogramming of immune cells, including increased glycolytic flux and OXPHOS, which drive the production of the pro-inflammatory cytokine IFN-γ. Consequently, reduced complosome activity translates into defects in normal monocyte activation, faulty Th1 and cytotoxic T lymphocyte responses and loss of protective tissue immunity. Intriguingly, neurological research has identified an unexpected connection between the physiological presence of innate and adaptive immune cells and certain cytokines, including IFN-γ, in and around the brain and normal brain function. In this opinion piece, we will first review the current state of research regarding complement driven metabolic reprogramming in the context of immune cell tissue entry and residency. We will then discuss how published work on the role of IFN-γ and T cells in the brain support a hypothesis that an evolutionarily conserved cooperation between the complosome, cell metabolism and IFN-γ regulates organismal behavior, as well as immunity.

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