Annexin-Mediated Regulation of the Peripheral Immune Response

Peripheral tolerance against self-antigens derived from apoptotic cells is essential for the organism. Apoptotic cells continuously evolve in the course of tissue turnover and are rapidly removed by phagocytes, e.g. dendritic cells (DC). Apoptotic cells have been shown to actively suppress DC in vitro, and engulfment of apoptotic cells is associated with inhibition of immune responses and the development of peripheral tolerance in vivo. However, specific molecules that mediate such tolerogenic effects of apoptotic cells have been largely elusive. Annexins are a family of evolutionary well conserved cytosolic proteins differentially expressed in various tissues. All annexins bind to negatively charged phospholipids in a calcium-dependent manner; however, the physiological function of the twelve vertebrate annexins has not been fully elucidated yet. We have shown that annexins, located in the cytosol of living cells, become translocated to the outer surface of apoptotic cells. Via their conserved core domain, annexins interact with DC and impose a tolerogenic phenotype on these DC, characterized by low expression of costimulatory surface molecules and inflammatory cytokines, reduced pro-inflammatory signal transduction and resistance to maturation. Such tolerogenic DC are able to actively induce so called "deleterious tolerance" by depleting autoreactive T cells. Thus, during the physiologic turnover of tissue cells the exposure of annexins on the surface of apoptotic cells acts as an immune checkpoint, which ensures tolerance to self-antigens derived from apoptotic cells.