CD47 in the Immune Response: Role of Thrombospondin and SIRP-α Reverse Signaling

Abstract

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.

CD47 deficiency confers cell and tissue radioprotection by activation of autophagy

“…1 Ligation of CD47 is known to induce apoptotic and nonapoptotic death in several cell types including activated T cells, 39 B-cell chronic lymphocytic leukemia, 40,41 promyelocytic leukemia, 42 multiple myeloma, 43 breast carcinoma, 44 and monocytes and dendritic cells. 45 Jurkat T cells deficient of CD47 are resistant to Fas-mediated cell death and are sensitized to death by ligation of Fas and re-expression of CD47.…”

“…45 Jurkat T cells deficient of CD47 are resistant to Fas-mediated cell death and are sensitized to death by ligation of Fas and re-expression of CD47. 39 Induction of T cell death by CD47 also involves activation of BNIP3. BNIP3 is a BCL2 family member that contains a BH3 domain with pro-apoptotic function, but BNIP3 also is essential for autophagy stimulated by 6-thioguanine or 5-fluorouracil.…”

Functional CD47/signal regulatory protein alpha (SIRPα) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo

“…CD47, a ubiquitously expressed Ig-like membrane protein, can interact with several other cell surface receptors (e.g., thrombospondin, integrins, and other members of the SIRP family) (20). These receptors can interact with CD47 in cis or in trans, and these interactions are described as a two-way exchange of information (21). The resulting complexity of CD47 biology may explain its broad-but not fully elucidated-role in hematopoietic and immune processes.…”

Masking Anti-Phagocytic Signal of Tumor by Pro-Phagocytic Signal-a Key to Immurement of Cancer Cell

“…CD47 is a cell surface transmembrane glycoprotein, in the immunoglobulin superfamily, involved in T-cell and dendritic cell activation [3], cell migration [4] and axon development [5]. In addition, it acts as a ligand for a signal regulatory protein-α (SIRP-α) expressed on macrophages and dendritic cells [6].…”