Complement modulation of T cell immune responses during homeostasis and disease

Clarke, Elizabeth V.; Tenner, Andrea J.

doi:10.1189/jlb.3mr0214-109r

Cited by 67 publications

(51 citation statements)

References 86 publications

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“…Thus, C1q–polarized phagocytic cells regulate T effector cell activation, essentially “sculpting” the adaptive immune response to avoid autoimmunity while clearing dying cells. While there have been some studies suggesting the possibility of a direct C1q interaction with T cells, more definitive investigations are needed (reviewed in (Clarke and Tenner, 2014)). The recent confirmation of the predominant role of C1q (rather than C1 activation and C3b deposition) on clearance and immunosuppression of apoptotic cells should direct therapeutic intervention in SLE and other autoimmune diseases (Colonna et al, 2016).…”

Section: Classical Functions: Complement Phagocytosis and Cytokinmentioning

confidence: 99%

C1q: A fresh look upon an old molecule

Thielens

Tedesco

Bohlson

et al. 2017

Molecular Immunology

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Originally discovered as part of C1, the initiation component of the classical complement pathway, it is now appreciated that C1q regulates a variety of cellular processes independent of complement activation. C1q is a complex glycoprotein assembled from 18 polypeptide chains, with a C-terminal globular head region that mediates recognition of diverse molecular structures, and an N-terminal collagen-like tail that mediates immune effector mechanisms. C1q mediates a variety of immunoregulatory functions considered important in the prevention of autoimmunity such as the enhancement of phagocytosis, regulation of cytokine production by antigen presenting cells, and subsequent alteration in T-lymphocyte maturation. Furthermore, recent advances indicate additional roles for C1q in diverse physiologic and pathologic processes including pregnancy, tissue repair, and cancer. Finally, C1q is emerging as a critical component of neuronal network refinement and homeostatic regulation within the central nervous system. This review summarizes the classical functions of C1q and reviews novel discoveries within the field.

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Section: Classical Functions: Complement Phagocytosis and Cytokinmentioning

confidence: 99%

C1q: A fresh look upon an old molecule

Thielens

Tedesco

Bohlson

et al. 2017

Molecular Immunology

Self Cite

181

139

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“…Recent studies have demonstrated its involvement in several physiological processes via binding with its specific receptors. 9 Among the processes induced by the non-classical functions of the C1q molecule, we find: the modulation of various immune cells, 10 the regulation of cell migration (chemotaxis), adhesion, survival and differentiation, 11 coagulation, 12 angiogenesis 13 and embryonic development, including neurological synapse function. 14 There is mounting evidence to support the idea that C1q and its receptors are also involved in the regulation of cancer.…”

Section: Introductionmentioning

confidence: 99%

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

et al. 2016

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There is an ever increasing amount of evidence to support the hypothesis that complement C1q, the first component of the classical complement pathway, is involved in the regulation of cancer growth, in addition to its role in fighting infections. It has been demonstrated that C1q is expressed in the microenvironment of various types of human tumors, including breast adenocarcinomas. This study compares carcinogenesis progression in C1q deficient (neuT-C1KO) and C1q competent neuT mice in order to investigate the role of C1q in mammary carcinogenesis. Significantly accelerated autochthonous neu C carcinoma progression was paralleled by accelerated spontaneous lung metastases occurrence in C1q deficient mice. Surprisingly, this effect was not caused by differences in the tumor-infiltrating cells or in the activation of the complement classical pathway, since neuT-C1KO mice did not display a reduction in C3 fragment deposition at the tumor site. By contrast, a significant higher number of intratumor blood vessels and a decrease in the activation of the tumor suppressor WW domain containing oxidoreductase (WWOX) were observed in tumors from neuT-C1KO as compare with neuT mice. In parallel, an increase in Her2/neu expression was observed on the membrane of tumor cells. Taken together, our findings suggest that C1q plays a direct role both on halting tumor angiogenesis and on inducing apoptosis in mammary cancer cells by coordinating the signal transduction pathways linked to WWOX and, furthermore, highlight the role of C1q in mammary tumor immune surveillance regardless of complement system activation.Abbreviations: BALB-C1KO, BALB/c mice deficient for the C1qA; BALB-C3KO, BALB/c mice deficient for C3; C1KO, C1q deficient; C1qR, C1q receptor; CR3, complement receptor 3; EMT, epithelial-to-mesenchymal transition; KLRK1 or NKG2D, killer cell lectin-like receptor subfamily K, member 1; MDCS, myeloid-derived suppressor cells; neuT, rat Her2/neu transgenic; neuT-BKO mice, neuT mice deficient in antibody production; neuT-C1KO mice, neuT mice deficient for the C1qA molecule; neuT-C3KO mice, neuT mice deficient for the C3 molecule; NK, natural killer; pWWOX, phospho WWOX; Treg, T regulatory; WWOX, WW domain containing oxidoreductase

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“…It mediates the immune response against pathogens, by directly tagging them for clearance, and by triggering the expression of pro-inflammatory molecules and the activation and recruitment of immune cells at the site of infection. Furthermore, it is involved in the maintenance of tissue homeostasis and adaptive immunity (Clarke and Tenner, 2014; Nonaka and Kimura, 2006; Ricklin et al, 2010). Complement components are predominantly synthesized in the liver and circulate in the blood stream until their activation (Ricklin et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Complement component C3aR constitutes a novel regulator for chick eye morphogenesis

Grajales-Esquivel

Luz-Madrigal

Bierly

et al. 2017

Developmental Biology

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Complement components have been implicated in a wide variety of functions including neurogenesis, proliferation, cell migration, differentiation, cancer, and more recently early development and regeneration. Following our initial observations indicating that C3a/C3aR signaling induces chick retina regeneration, we analyzed its role in chick eye morphogenesis. During eye development, the optic vesicle (OV) invaginates to generate a bilayer optic cup (OC) that gives rise to the retinal pigmented epithelium (RPE) and neural retina. We show by immunofluorescence staining that C3 and the receptor for C3a (the cleaved and active form of C3), C3aR, are present in chick embryos during eye morphogenesis in the OV and OC. Interestingly, C3aR is mainly localized in the nuclear compartment at the OC stage. Loss of function studies at the OV stage using morpholinos or a blocking antibody targeting the C3aR (anti-C3aR Ab), causes eye defects such as microphthalmia and defects in the ventral portion of the eye that result in coloboma. Such defects were not observed when C3aR was disrupted at the OC stage. Histological analysis demonstrated that microphthalmic eyes were unable to generate a normal optic stalk or a closed OC. The dorsal/ventral patterning defects were accompanied by an expansion of the ventral markers Pax2, cVax and retinoic acid synthesizing enzyme raldh-3 (aldh1a3) domains, an absence of the dorsal expression of Tbx5 and raldh-1 (aldh1a1) and a re-specification of the ventral RPE to neuroepithelium. In addition, the eyes showed overall decreased expression of Gli1 and a change in distribution of nuclear β-catenin, suggesting that Shh and Wnt pathways have been affected. Finally, we observed prominent cell death along with a decrease in proliferating cells, indicating that both processes contribute to the microphthalmic phenotype. Together our results show that C3aR is necessary for the proper morphogenesis of the OC. This is the first report implicating C3aR in eye development, revealing an unsuspected hitherto regulator for proper chick eye morphogenesis.

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Complement modulation of T cell immune responses during homeostasis and disease

Cited by 67 publications

References 86 publications

C1q: A fresh look upon an old molecule

C1q: A fresh look upon an old molecule

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

Complement component C3aR constitutes a novel regulator for chick eye morphogenesis

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