The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation

Choileáin, Siobhán Ní; Weyand, Nathan J.; Neumann, Christian; Thomas, Jean‐Claude; So, Magdalene; Astier, Anne

doi:10.1371/journal.pone.0016287

Cited by 58 publications

(108 citation statements)

References 41 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The switch from high to low glycolysis and OXPHOS, on the other hand, is mediated by CD46 isoforms expressing CYT-2, which again become the predominant CD46 isoforms in contracting T cells (28, 31). Moreover, the intracellular tails of CD46 are processed by γ-secretase (88), and we demonstrated that nuclear translocation of both domains occurs and that particularly translocation of CYT-1 into the nucleus is required for Th1 induction (28). These observations make it a possibility that CD46 intracellular domains may interact with and modulate the function of TF complexes (possibly as activators and/or inhibitors) and via this directly control metabolic pathways.…”

Section: Complement and Metabolismmentioning

confidence: 93%

“…Non-activated CD4 + T cells express predominantly CD46-CYT-2 (31) while TCR activation leads to the upregulation of the CYT-1-bearing CD46 isoform. And it is CYT-1 that drives the expression of GLUT1, LAT1, and LAMTOR5—all required for mTORC1 assembly and activation with subsequent increased glycolysis, OXPHOS, and IFN-γ secretion (28, 88). The switch from high to low glycolysis and OXPHOS, on the other hand, is mediated by CD46 isoforms expressing CYT-2, which again become the predominant CD46 isoforms in contracting T cells (28, 31).…”

Section: Complement and Metabolismmentioning

confidence: 99%

See 1 more Smart Citation

Keeping It All Going—Complement Meets Metabolism

Kolev

Kemper²

2017

Front. Immunol.

375

553

View full text Add to dashboard Cite

The complement system is an evolutionary old and crucial component of innate immunity, which is key to the detection and removal of invading pathogens. It was initially discovered as a liver-derived sentinel system circulating in serum, the lymph, and interstitial fluids that mediate the opsonization and lytic killing of bacteria, fungi, and viruses and the initiation of the general inflammatory responses. Although work performed specifically in the last five decades identified complement also as a critical instructor of adaptive immunity—indicating that complement’s function is likely broader than initially anticipated—the dominant opinion among researchers and clinicians was that the key complement functions were in principle defined. However, there is now a growing realization that complement activity goes well beyond “classic” immune functions and that this system is also required for normal (neuronal) development and activity and general cell and tissue integrity and homeostasis. Furthermore, the recent discovery that complement activation is not confined to the extracellular space but occurs within cells led to the surprising understanding that complement is involved in the regulation of basic processes of the cell, particularly those of metabolic nature—mostly via novel crosstalks between complement and intracellular sensor, and effector, pathways that had been overlooked because of their spatial separation. These paradigm shifts in the field led to a renaissance in complement research and provide new platforms to now better understand the molecular pathways underlying the wide-reaching effects of complement functions in immunity and beyond. In this review, we will cover the current knowledge about complement’s emerging relationship with the cellular metabolism machinery with a focus on the functional differences between serum-circulating versus intracellularly active complement during normal cell survival and induction of effector functions. We will also discuss how taking a closer look into the evolution of key complement components not only made the functional connection between complement and metabolism rather “predictable” but how it may also give clues for the discovery of additional roles for complement in basic cellular processes.

show abstract

Section: Complement and Metabolismmentioning

confidence: 93%

Section: Complement and Metabolismmentioning

confidence: 99%

Keeping It All Going—Complement Meets Metabolism

Kolev

Kemper²

2017

Front. Immunol.

375

553

View full text Add to dashboard Cite

show abstract

“…The enzymatic processing of CD46 is a crucial feature of CD46-mediated pathway that is involved in regulating T cell function. CD46 surface expression is strongly downregulated upon its own triggering, partly due to MMP cleavage of its ectodomain (9–11). This is followed by cleavage by gamma-secretase of the two cytoplasmic tails of CD46, which is important to initiate and terminate T cell responses (11, 12).…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E2 Affects T Cell Responses through Modulation of CD46 Expression

Kickler

Maltby

Choileáin

et al. 2012

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The ubiquitous protein CD46, a regulator of complement activity, promotes T cell activation and differentiation towards a regulatory Tr1-like phenotype. CD46-mediated differentiation pathway is defective in several chronic inflammatory diseases, underlying the importance of CD46 in controlling T cell function and the need to understand its regulatory mechanisms. Using an RNAi-based screening approach in primary T cells, we have identified that two members of the G-protein coupled receptor (GPCR) kinases were involved in regulating CD46 expression at the surface of activated cells. We have investigated the role of prostaglandin E2 (PGE2), which binds to the E-prostanoid family of GPCRs through four subtypes of receptors called EP1-4, in the regulation of CD46 expression and function. Conflicting roles of PGE2 in T cell functions have been reported, and the reasons for these apparent discrepancies are not well understood. We show that addition of PGE2 strongly downregulates CD46 expression in activated T cells. Moreover, PGE2 differentially affects T cell activation, cytokine production and phenotype depending on the activation signals received by the T cells. This was correlated with a distinct pattern of the PGE2 receptors induced, with EP4 being preferentially induced by CD46 activation. Indeed, addition of an EP4 antagonist could reverse the effects observed on cytokine production observed following CD46 costimulation. These data demonstrate a novel role of the PGE2-EP4-GRK axis in CD46 functions, which might at least partly explain the diverse roles of PGE2 in T cell functions.

show abstract

“…Because of alternative splicing, multiple isoforms are produced, which include two distinct intracytoplasmic tails 20 . In vitro studies using primary human T cells showed the antagonistic effects of CD46 cytoplasmic tails in T‐cell activation and cytokine production 21 , 22 . These studies also illustrated the importance of CD46 processing for its function.…”

mentioning

confidence: 88%

“…Notably, inhibition of MMPs led to decreased IL‐10 production by CD46‐costimulated T cells. Moreover, CD46 tail processing allows T‐cell activation as well as T‐cell termination, and therefore is key to ensuring T‐cell homeostasis 21 , 22 . Expression of CD46 at the surface of T cells is further regulated by a variety of mediators, such as vitamin D 23 and prostaglandin E2 24 .…”

mentioning

confidence: 99%

Monocyte:T‐cell interaction regulates human T‐cell activation through a CD28/CD46 crosstalk

et al. 2015

Self Cite

View full text Add to dashboard Cite

T cell activation requires engagement of the T cell receptor and of at least one costimulatory molecule. The key role of CD28 in inducing T cell activation has been reported several decades ago and the molecular mechanisms involved well described. The complement regulator CD46 also acts as a costimulatory molecule for T cells but, in contrast to CD28, has the ability to drive T cell differentiation from producing some IFNγ to secreting some potent anti-inflammatory IL-10, acquiring a so-called Type I regulatory phenotype (Tr1). Proteolytic cleavage of CD46 occurs upon costimulation and is important for T cell activation and IL-10 production. The observation that CD46 cleavage was reduced when PBMC were costimulated compared to purified naive T cells led us to hypothesize that interactions between different cell types within the PBMC were able to modulate the CD46 pathway. We show that CD46 downregulation is also reduced when CD4+ T cells are co-cultured with autologous monocytes. Indeed, monocyte:T cell co-cultures impaired CD46–mediated T cell differentiation and coactivation, by reducing downregulation of surface CD46, lowering induction of the early activation marker CD69, as well as reducing the levels of IL-10 secretion. Blocking of CD86 could partly restore CD69 expression and cytokine secretion, demonstrating that the CD28-CD86 pathway regulates CD46 activation. Direct concomitant ligation of CD28 and CD46 on CD4+ T cells also modulated CD46 expression and regulated cytokine production. These data identify a crosstalk between two main costimulatory pathways and provide novel insights into the regulation of human T cell activation.

show abstract

The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation

Cited by 58 publications

References 41 publications

Keeping It All Going—Complement Meets Metabolism

Keeping It All Going—Complement Meets Metabolism

Prostaglandin E2 Affects T Cell Responses through Modulation of CD46 Expression

Monocyte:T‐cell interaction regulates human T‐cell activation through a CD28/CD46 crosstalk

Contact Info

Product

Resources

About