Key Points
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The complement system is necessary for the induction of optimal T-cell effector function. In complement component 3 (C3)-deficient mice, CD4+ T-cell responses to viruses are impaired and the optimal CD8+ T-cell responses are not induced.
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The complement system influences priming of T-cell responses by facilitating antigen-presenting cell (APC)–T-cell interactions. To carry out this task, APCs express various receptors for complement ligands.
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Deficiencies in complement components or receptor function hinder T-cell-dependent processes, whereas deficiencies in regulators lead to a more robust T-cell response. Alterations in this fine balance have a role in immune-mediated diseases.
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Complement regulators have a role in the controlled induction of T-cell apoptosis (and therefore the contraction of an effector response) by modulating apoptotic signals.
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Crosslinking of CD3 and the complement regulatory protein CD46 induces a regulatory T-cell phenotype in humans. These cells synthesize large amounts of interleukin-10 and granzyme B, through which these complement-induced regulatory T cells can inhibit effector T-cell proliferation and kill many types of activated, immunocompetent cells.
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There are substantial differences in the structure and expression profile of complement receptors and regulators between mouse and humans.
Abstract
The complement system was traditionally known as an effector arm of humoral immunity. Today we also recognize it as a main element of the innate immune system. In blood and other body fluids complement is a first line of defence against pathogens, because it becomes fully active within seconds. Active complement fragments attach to the invading pathogen to promote opsonization and lysis, triggering a local inflammatory response. This Review focuses on the evolving role of the complement system in the regulation of T-cell responses, from directing the initiation phase, through driving lineage commitment, to regulating the contraction phase.
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Acknowledgements
We thank K. Murphy, S. Virgin, W. Barchet and the Immunology community at Washington University for their support. We also thank M. Bogacki and L. Whiteley for secretarial assistance.
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Glossary
- Opsonins
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Proteins that bind to the surface of a particle and enhance its uptake by a phagocyte. Opsonins include IgG and complement activation fragments (including C4b, C3b, iC3b, C3dg and C3d).
- Anaphylatoxins
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The pro-inflammatory complement activation fragments C3a and C5a. These mediate an inflammatory response through cell activation to induce, for example, chemotaxis and histamine release.
- Complement-fixing antibodies
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Not all antibodies fix or activate complement. In humans, IgM and the IgG subclasses IgG1 and IgG3 readily fix complement, whereas IgG2 is less effective. The IgG subclass IgG4 and other classes of immunoglobulin do not fix complement or activate the classical complement pathway.
- Immune adherence
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The binding of antigens or immune complexes, opsonized with complement ligands, to complement receptors expressed on cells such as erythrocytes, B cells, follicular dendritic cells, monocytes and macrophages.
- Lytic mechanism
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The lysis of microbes or cells through the formation of the membrane-attack complex by the terminal components of the complement cascade C5b–C9.
- Mixed lymphocyte reaction
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An in vitro assay to measure the reactivity of alloreactive T cells from one donor to the MHC antigens on peripheral blood cells or antigen-presenting cells from another donor.
- Experimental autoimmune encephalomyelitis
-
An experimental model of the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.
- Primarily vascularized graft
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A type of transplantation in which the recipient's vasculature is connected to the vessels of the donor graft.
- Ischaemia-reperfusion injury
-
Cellular damage caused by the return of a blood supply to a tissue after a period of inadequate blood supply. The absence of oxygen and nutrients causes cellular damage such that restoration of the blood flow results in inflammation.
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Kemper, C., Atkinson, J. T-cell regulation: with complements from innate immunity. Nat Rev Immunol 7, 9–18 (2007). https://doi.org/10.1038/nri1994
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DOI: https://doi.org/10.1038/nri1994