Cutting Edge: Receptors for C3a and C5a Modulate Stability of Alloantigen-Reactive Induced Regulatory T Cells

Touw, William van der; Cravedi, Paolo; Kwan, W. H.; Paz-Artal, Estela; Mérad, Miriam; Heeger, Peter S.

doi:10.4049/jimmunol.1300847

Cited by 108 publications

(95 citation statements)

References 25 publications

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“…Overwhelming evidence has accumulated that C5aR1 activation regulates CD4 + T cell survival, proliferation, and differentiation into Th1 (35), Th2 (36), or Th17 (70-72) effector cells, as well as induced (31,70,73) and natural (57) regulatory CD4 + T cells. However, conflicting results exist about whether such regulation is driven primarily by the impact of C5a on APC activation or whether C5a can directly modulate T cell activation.…”

Section: Discussionmentioning

confidence: 99%

Monitoring and Cell-Specific Deletion of C5aR1 Using a Novel Floxed GFP-C5aR1 Reporter Knock-in Mouse

Karsten

Laumonnier

Eurich

et al. 2015

The Journal of Immunology

102

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Many of the biological properties of C5a are mediated through activation of its receptor (C5aR1), the expression of which has been demonstrated convincingly on myeloid cells, such as neutrophils, monocytes, and macrophages. In contrast, conflicting results exist regarding C5aR1 expression in dendritic cells (DCs) and lymphoid lineage cells. In this article, we report the generation of a floxed GFP-C5aR1 reporter knock-in mouse. Using this mouse strain, we confirmed strong C5aR1 expression in neutrophils from bone marrow, blood, lung, and spleen, as well as in peritoneal macrophages. Further, we show C5aR1 expression in lung eosinophils, lung- and lamina propria–resident and alveolar macrophages, bone marrow–derived DCs, and lung-resident CD11b+ and monocyte-derived DCs, whereas intestinal and pulmonary CD103+ DCs stained negative. Also, some splenic NKT cells expressed GFP, whereas naive NK cells and B2 cells lacked GFP expression. Finally, we did not observe any C5aR1 expression in naive or activated CD4+ Th cells in vitro or in vivo. Mating the floxed GFP-C5aR1 mouse strain with LysMCre mice, we were able to specifically delete C5aR1 in neutrophils and macrophages, whereas C5aR1 expression was retained in DCs. In summary, our findings suggest that C5aR1 expression in mice is largely restricted to cells of the myeloid lineage. The novel floxed C5aR1 reporter knock-in mouse will prove useful to track C5aR1 expression in experimental models of acute and chronic inflammation and to conditionally delete C5aR1 in immune cells.

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Section: Discussionmentioning

confidence: 99%

Monitoring and Cell-Specific Deletion of C5aR1 Using a Novel Floxed GFP-C5aR1 Reporter Knock-in Mouse

Karsten

Laumonnier

Eurich

et al. 2015

The Journal of Immunology

102

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“…Interestingly, the plasma concentration of C5a was significantly lower in KD patients than that in febrile controls. This decrease in plasma level of C5a might have resulted from rapid combination with C5aR in peripheral blood (20). It has also been postulated that decreased levels of C5a may protect against the inflammatory response (21).…”

Section: Discussionmentioning

confidence: 99%

Early decreased plasma levels of factor B and C5a are important biomarkers in children with Kawasaki disease

Zou

Song

et al. 2015

Pediatr Res

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Background:The mechanisms underpinning Kawasaki disease (KD) are incompletely understood. There is an unmet need for specific biomarkers for the early diagnosis of KD. Methods: Eighty-five KD patients suffering from acute-phase and subacute-phase KD, 40 healthy children, and 40 febrile children comprised the study cohort. An enzyme-linked immunosorbent assay was used to measure plasma levels of C1q, C1q-circulating immune complex (C1q-CIC), mannan-binding lectin-associated serine protease (MASP)-1, factor B, C4d, C3d, C5a, C5b-9 and CD59. results: Plasma concentrations of factor B and C5a in the acute phase were lower than those in healthy and febrile control groups (all P < 0.05). Compared with acute-phase KD patients, plasma concentrations of C1q, factor B, and C3d in KD patients were increased significantly (P < 0.05), but those of C4d, MASP-1 and CD59 decreased significantly (P < 0.05), in patients with sub-acute KD. conclusion: These data suggest that more than one pathway in the complement system is activated in KD. Importantly, decreased plasma concentrations of factor B and C5a in the acute phase (6-10 d) could be employed as biomarkers for the early diagnosis of KD. k awasaki disease (KD) is an acute, self-limiting, nonspecific systemic vascular inflammatory syndrome. KD is considered to be caused by infectious agents in genetically susceptible children. The diagnosis of KD is dependent upon clinical manifestations; definitive diagnostic markers are lacking. The pathogenesis of KD is characterized by immune injury to endothelial cells (1) that results in systemic vasculitis or aneurysms in coronary arteries (2).Vascular endothelial cells are a source of complement and complement regulatory factors. Activated complement can form complement fragments (e.g., C3, C4d, Bb) and the membrane attack complex (MAC) on the cell surface (3). The MAC can mediate the inflammatory response by killing anucleate cells and bacteria, as well as causing cells to secrete a large number of cytokines and growth factors (4). Animal studies have shown that coronary atherosclerotic lesions appear not only during complement activation, but also during complement deposition, which results in tissue injury (5). It also has been demonstrated that complement components are accumulated in cryoglobulinemic vasculitis (6). Other studies have reported dysfunction of vascular endothelial cells (7) and the classical pathway of complement activation in all three layers of aneurysms (8).With the evidence stated above, we speculated that activation of the complement system might be involved in the pathogenesis of KD, and that activated complement factors could be employed as early diagnostic markers for KD. To test this hypothesis, we investigated plasma levels of various complement components in children with acute KD and subacute KD. RESULTS Changes in Plasma Concentrations of Complement FactorsC1q and C1q-circulating immune complex (C1q-CIC). C1q is a factor of the classical pathway of complement activation. The plasma level of C1q was sig...

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“…Data published in 2013 indicate that complement also regulates Treg induction, function, and stability (12,30) (Figure 2). Our group showed that peripheral, murine, natural regulatory T cells (nTregs) express C3aR and C5aR and that signaling through these receptors inhibits Treg function (11).…”

Section: Links Between Complement and Adaptive Immunitymentioning

confidence: 98%

“…Mechanisms involve C3a/C5a-induced phosphorylation of AKT and, as a consequence, phosphorylation of the transcription factor Foxo1, which results in lowered nTreg Foxp3 expression. Two additional sets of data showed that genetic deficiency or pharmacologic blockade of C3aR/C5aR signaling augments murine-induced regulatory T cell (iTreg) generation, stabilizes Foxp3 expression, and resists iTreg conversion to IFN-g/TNF-a-producing effector T cells (12,30). Pharmacologic antagonists to human C3aR and C5aR also augment in vitro generation and stability of human iTreg from naïve precursors (12,30).…”

Section: Links Between Complement and Adaptive Immunitymentioning

confidence: 99%

Molecules Great and Small

Mathern

Heeger

2015

Clinical Journal of the American Society of Nephrology

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242

192

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The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.

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Cutting Edge: Receptors for C3a and C5a Modulate Stability of Alloantigen-Reactive Induced Regulatory T Cells

Cited by 108 publications

References 25 publications

Monitoring and Cell-Specific Deletion of C5aR1 Using a Novel Floxed GFP-C5aR1 Reporter Knock-in Mouse

Monitoring and Cell-Specific Deletion of C5aR1 Using a Novel Floxed GFP-C5aR1 Reporter Knock-in Mouse

Early decreased plasma levels of factor B and C5a are important biomarkers in children with Kawasaki disease

Molecules Great and Small

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