Complement Regulation of T-Cell Alloimmunity

Abstract

Summary 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.

Effects of DNA Methylation on Progression to Interstitial Fibrosis and Tubular Atrophy in Renal Allograft Biopsies: A Multi-Omics Approach

“…The role of complement system in long-term kidney injury was also observed with genes like C3AR1, C5AR1, FCGR2A . Due to the observed hypo-methylation of the complement receptors, they could be constitutively expressed on macrophages and CD4+ T cells and stimulates maturation, cytokine production and costimulatory molecule expression (67). In addition to immune-mediated damage, genes like FABP1 and Proc that have been previously shown to have protective function and recovery in kidney post-ischemic injury (68–70) were hyper-methylated (DNAm array) and downregulated (mRNA array).…”

Complement proteins C7 and CFH control the stemness of liver cancer cells via LSF-1

“…In contrast, the role of C7 in cancer cells is still not well understood. There are known receptors of complement C3a–C5a, and some are functionally characterized but mainly related to the innate immune system [26–28]. Therefore, it is unclear if C7 or CFH can be secreted and internalized into other cancer cells in order to function as a stemness regulator.…”

Decreased expression of IL-33 in immune thrombocytopenia

“…T cells play a critical role in maintaining immunity homeostasis [14]. T cells are grouped into the following subsets based on their function and surface markers: cytotoxic T cells, helper T cells, regulatory T cells, memory T cells, etc.…”