CD47 in the immune response: role of thrombospondin and SIRP-alpha reverse signaling

The past decades have been marked by spectacular progress towards understanding how dendritic cells (DCs) interact with T cells to elicit protective immune responses to fight infectious diseases and cancer. DCs that are lying at the interface between innate and adaptive immunity, are educated in peripheral tissues prior to their journey to the secondary lymphoid organs (SLO) whereby they dictate different classes of T cell responses. Uncontrolled or unwanted inflammatory responses are the price to pay to eliminate pathogens. However, if not self-limited, they may induce collateral damages that result in chronic inflammation often associated with autoimmune disorders. CD47 and its two ligands, i.e. thrombospondin 1 (TSP-1) and SIRP-alpha, were identified as a previously unappreciated inhibitory axis of DC and T cell functions. TSP-1 is predominantly a negative regulator of DC and T cell function while basal SIRP-alpha ligation on APC by CD47 enforces tolerance. Yet, CD47/SIRP-alpha interaction positively controls DC and innate cell transendothelial migration. Due to the promiscuity of the protein interactions for CD47 and its ligands, it is quite interesting to note that deletion of the CD47 gene in mice largely agrees with the in vitro data with human cells. In fact, the well-conserved tissue distribution of CD47 and SIRP-alpha across species may facilitate the transition from bench to bedside. We thus propose CD47/TSP-1/SIRP-alpha axis as an important sensor to maintain homeostasis and regulate innate and adaptive immune responses.