Complement regulation of T-cell alloimmunity.

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.