title: Complement regulation of T-cell alloimmunity.
abstract: Complement proteins are generated both by the liver (systemic compartment) and by peripheral tissue-resident cells and migratory immune cells (local compartment). The immune cell-derived, alternative pathway complement components activate spontaneously, yielding local, but not systemic, production of C3a and C5a. These anaphylatoxins bind to their respective G-protein-coupled receptors, the C3a receptor and the C5a receptor, expressed on T cells and antigen-presenting cells, leading to their reciprocal activation and driving T-cell differentiation, expansion, and survival. Complement deficiency or blockade attenuates T-cell-mediated autoimmunity and delays allograft rejection in mice. Increasing complement activation, achieved by genetic removal of the complement regulatory protein decay accelerating factor, enhances murine T-cell immunity and accelerates allograft rejection. Signaling through the C3a receptor and the C5a receptor reduces suppressive activity of natural regulatory T cells and the generation and stability of induced regulatory T cells. The concepts, initially generated in mice, recently were confirmed in human immune cells, supporting the need for testing of complement targeting therapies in organ transplants patients.
authors.affiliation: Department of Medicine, Recanati Miller Transplant Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cravedi
authors.forename: William
authors.initials: W
authors.lastname: van der Touw
authors.forename: Peter S
authors.initials: PS
authors.lastname: Heeger
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015551:Autoimmunity / Q000502:physiology*; D003167:Complement Activation / Q000502:physiology; D051056:Complement Inactivating Agents / Q000494:pharmacology; D003165:Complement System Proteins / Q000378:metabolism*; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D051056:Complement Inactivating Agents; D003165:Complement System Proteins
keywords: Allograft rejection; T cells; complement; costimulation; transplantation