CD46 is a potent co-stimulatory receptor for expansion of human IFN-γ-producing CD8 +  T cells

Hansen, Aida S.; Slater, Josefine; Biltoft, Mette; Bundgaard, Bettina; Møller, Bjarne Kuno; Höllsberg, Per

doi:10.1016/j.imlet.2018.06.003

Cited by 7 publications

(8 citation statements)

References 28 publications

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“…However, this study did not deplete CD56 + cells (natural killer (NK) and NK T cells) from their cultures, which impact heavily on CD8 + T-cell function, and could explain the discrepancy in observed outcomes of CD46 co-stimulation of CTLs between the two studies. This is supported by recent work published by Hansen and colleagues that confirms our finding as this group also observed increased IFN-γ secretion by human CTLs activated in the presence of anti-CD46 antibodies 37 . Cytotoxic activity, or CD46-driven downstream signals, however, were not explored in this work.…”

Section: Discussionsupporting

confidence: 93%

Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism

et al. 2018

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The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men.

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Section: Discussionsupporting

confidence: 93%

Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism

et al. 2018

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“…It has been observed that CD46 can induce low levels of IL-10 in CTLs, but the amounts generated are small compared to those observed in CD4 + /Th1 cells and a co-induction of suppressive activity in CTLs via CD46 was not investigated. 85…”

Section: The Complosome and Th1 Cell Contractionmentioning

confidence: 99%

“…Similarly, a role for CD46 or other complosome components during CD8 + T cell contraction remains to be investigated. It has been observed that CD46 can induce low levels of IL‐10 in CTLs, but the amounts generated are small compared to those observed in CD4 + /Th1 cells and a co‐induction of suppressive activity in CTLs via CD46 was not investigated . Nonetheless, intracellular complement can, analogously to what has been described in human CD4 + T cells, also exert negative control over CD8 + T cells.…”

Section: The Complosome In Human T Cell Metabolismmentioning

confidence: 99%

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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“…TCR and CD28 stimulation increases complosome activation and leads to autocrine engagement of CD46 also in these T cells (Figure 1B). However, and in contrast to CD4 + T cells, where CD46 signals are absolutely required for IFN-γ production and Th1 induction, in CD8 + T cells CD46 signals are not obligatory but rather support optimal CTL effector activity induced by TCR and CD28 engagement [12,53]. More specifically, in human CD8 + T cells, CD46 costimulation augments both CTL effector cytokine secretion (IFN-γ and TNF-α) and their ability to kill target cells, with concomitant increases in degranulation and granzyme B secretion.…”

Section: The Complosome and Ctl Activitymentioning

confidence: 99%

“…Similarly, a role for CD46 or other complosome components during CD8 + T cell contraction remains to be established. Of note, one study suggests that CD46 fails to drive IL-10 in CTLs, further underpinning differences in complosome activities between CD4 + and CD8 + T cells [53]. Nonetheless, there is indication that intracellular complement can, analogously to what is observed in CD4 + T cells, also exert negative control over CD8 + T cells to dampen CTL responses and prevent immunopathologies.…”

Section: The Complosome and Ctl Activitymentioning

confidence: 99%

Complement and T Cell Metabolism: Food for Thought

West

Kemper

2019

Immunometabolism

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The classical complement system is engrained in the mind of scientists and clinicians as a blood-operative key arm of innate immunity, critically required for the protection against invading pathogens. Recent work, however, has defined a novel and unexpected role for an intracellular complement system-the complosome-in the regulation of key metabolic events that underlie peripheral human T cell survival as well as the induction and cessation of their effector functions. This review summarizes the current knowledge about the emerging vital role of the complosome in T cell metabolism and discusses how viewing the evolution of the complement system from an "unconventional" vantage point could logically account for the development of its metabolic activities.

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CD46 is a potent co-stimulatory receptor for expansion of human IFN-γ-producing CD8 + T cells

Cited by 7 publications

References 28 publications

Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism

Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism

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

Complement and T Cell Metabolism: Food for Thought

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